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I have read this post but am still slightly confused about this. Do tissues in the human body not all develop from the same cell(s) in the embryo? If so, I do not see how the cell 'mosaic' would be grainy enough to mask the fact that half of the female's cells are not working properly. For example, all liver cells come from the same cell in the embryo which has an inactivated X. In that case, there is a 50% chance that the females liver is dysfunctional. So I would predict that some females would exhibit X-linked disorers even if they are heterozygous, but I haven't heard of this being the case…
Barr bodies (X-chromosome inactivation) don't form in the initial fertilized embryo - it's not that one X-chromosome is inactivated, and then that same inactivation is passed down to daughter cells. Rather, X-chromosome inactivation occurs on a cell-by-cell basis in differentiated cells. Note how the accepted answer to the question you linked mentions that different cell lineages will have different X-chromosome inactivation patterns - in other words, inactivation occurs later in the differentiation and proliferation processes than I think you might be assuming.
To use your example: the liver cells do not all derive from a pluripotent (undifferentiated) cell with one inactivated X-chromosome, but instead derive from said pluripotent cell, and then undergo X-chromosome inactivation.
Although the jury is out, scientifically speaking, on the mechanisms of selection of the X-chromosome to be inactivated, it's been postulated that some sort of decision-making may occur on this cellular level, resulting in a higher likelihood of inactivating the damaged or deleterious chromosome, if one is present.
Regardless, as the accepted answer to the question you linked mentions, the 50% of functional cells that would result from chance or random X-chromosome inactivation tends to be sufficient for the body's needs.
X inactivation plays a major role in the gender bias in somatic expansion in a mouse model of the fragile X-related disorders: implications for the mechanism of repeat expansion
1 Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA, and
2 Department of Medical Biochemistry, University of Cape Town, Cape Town, South Africa
1 Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA, and
1 Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA, and
Sex-Linked and Nontraditional Modes of Inheritance
The previous chapter dealt with diseases that are inherited in patterns that were first elucidated by Gregor Mendel. In this chapter we discuss disease-causing mutations that are inherited in ways that were unknown to Mendel and are thus sometimes termed nonmendelian.
The first mutations to be discussed are DNA variants of the sex chromosomes (X and Y), known as sex-linked mutations. The human X chromosome is large, containing about 5% of the nuclear genome’s DNA (approximately 155 million base pairs [155 megabases, 155 Mb]). Nearly 1300 genes have been localized to the X chromosome, and the diseases caused by these genes are said to be X-linked. In contrast to the X chromosome, the Y chromosome is quite small (60 Mb) and contains only a few dozen genes.
Another group of disease-causing mutations is located in the mitochondrial genome, which is inherited only from one’s mother. Mitochondrial diseases thus display a unique pattern of inheritance in families. Extensive analyses have revealed a growing number of disease-causing mutations in the mitochondrial genome.
Finally, we discuss two processes that have been elucidated only in the past two to three decades: anticipation and imprinting. Anticipation refers to earlier age-of-onset of some genetic diseases in more recent generations of families. Imprinting refers to the fact that some genes are expressed only on paternally transmitted chromosomes and others are expressed only on maternally transmitted chromosomes. Our understanding of both of these processes has been greatly enhanced by detailed molecular analyses of humans and model organisms.
The X chromosome contains many important protein-coding genes, and it has long been known that human females have two X chromosomes and males have only one. Thus females have two copies of each X-linked gene, and males have only one copy. Yet males and females do not differ in terms of the amounts of protein products (e.g., enzyme levels) encoded by most of these genes. What could account for this?
In the early 1960s Mary Lyon hypothesized that one X chromosome in each somatic cell of the female is inactivated. This would result in dosage compensation, an equalization of the amount of X-linked gene products in males and females. The Lyon hypothesis stated that X inactivation occurs early in female embryonic development and that the X chromosome contributed by the father is inactivated in some cells, whereas in other cells the X chromosome contributed by the mother is inactivated. In each cell, one of the two X chromosomes is chosen at random for inactivation, so the maternally and paternally transmitted X chromosomes are each inactivated in about half of the embryo’s cells. Inactivation, like gamete transmission, is analogous to a coin-tossing experiment. Once an X chromosome is inactivated in a cell, it will remain inactive in all descendants of that cell. X inactivation is therefore a randomly determined, but fixed (or permanent) process. As a result of X inactivation, all normal females have two distinct populations of cells: one population has an active paternally derived X chromosome, and the other has an active maternally derived X chromosome. ( Fig. 5.1 provides a summary of this process.) Because they have two populations of cells, females are mosaics (see Chapter 4 ) for X chromosome activity. Males, having only one copy of the X chromosome, are not mosaics but are hemizygous for the X chromosome ( hemi means “half”).
The Lyon hypothesis states that one X chromosome in each cell is randomly inactivated early in the embryonic development of females. This ensures that females, who have two copies of the X chromosome, will produce X-linked gene products in quantities roughly similar to those produced in males (dosage compensation).
The Lyon hypothesis relied on several pieces of evidence, most of which were derived from animal studies. First, it was known that females are typically mosaics for some X-linked traits and males are not. For example, female “calico” cats have alternating black and orange patches of fur that correspond to two populations of cells: one that contains X chromosomes in which an “orange” allele is active and one that contains X chromosomes in which a “black” allele is active. Male cats of this breed do not exhibit alternating colors and have either black or orange patches of fur. Another example seen in humans is X-linked ocular albinism. This is an X-linked recessive condition characterized by a lack of melanin production in the retina and by ocular problems such as nystagmus (rapid involuntary eye movements) and decreased visual acuity. Males who inherit the mutation show a relatively uniform lack of melanin in their retinas, whereas female heterozygotes exhibit alternating patches of pigmented and nonpigmented tissue ( Fig. 5.2 ).
The Lyon hypothesis was also supported by biochemical evidence. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is encoded by a gene on the X chromosome and is present in equal quantities in males and females (dosage compensation). In females who are heterozygous for two common G6PD alleles (labeled A and B ), some skin cells produce only the A variant of the enzyme and others produce only the B variant. This is further proof of X chromosome mosaicism in females.
Finally, cytogenetic studies in the 1940s showed that interphase cells of female cats often contained a densely staining chromatin mass in their nuclei. These masses were not seen in males. They were termed Barr bodies, after Murray Barr, one of the scientists who described them. Barr and his colleague Ewart Bertram hypothesized that the Barr body represented a highly condensed X chromosome. It is now known that Barr and Bertram were correct and that the inactive X chromosome is observable as a Barr body in the somatic cells of normal females. Its condensed state is correlated with reduced transcriptional activity, and its DNA is replicated later in the S phase than that of other chromosomes.
The Lyon hypothesis is supported by cytogenetic evidence: Barr bodies, which are inactive X chromosomes, are seen only in cells with two or more X chromosomes. It is also supported by biochemical and animal studies that reveal mosaicism of X-linked traits in female heterozygotes.
Further study has largely verified the Lyon hypothesis. Messenger RNA (mRNA) is transcribed from only one X chromosome in each somatic cell of a normal female. The inactivation process takes place within approximately 7 to 10 days after fertilization, when the embryonic inner-cell mass contains no more than a few dozen cells. Inactivation is initiated in a single 1-Mb region on the X chromosome long arm, the X inactivation center, and then spreads along the chromosome. Although inactivation is random among cells that make up the embryo itself, only the paternally derived X chromosome is inactivated in cells that will become extraembryonic tissue (e.g., the placenta). X inactivation is permanent for all somatic cells in the female, but the inactive X chromosome must later become reactivated in the female’s germline so that each of her egg cells will receive one active copy of the X chromosome.
An important implication of the Lyon hypothesis is that the number of Barr bodies in somatic cells is always one less than the number of X chromosomes. Normal females have one Barr body in each somatic cell, and normal males have none. Females with Turner syndrome (see Chapter 6 ), having only one X chromosome, have no Barr bodies. Males with Klinefelter syndrome (two X chromosomes and a Y chromosome) have one Barr body in their somatic cells, and females who have three X chromosomes per cell have two Barr bodies in each somatic cell. This pattern leads to another question: if the extra X chromosomes are inactivated, why aren’t people with extra (or missing) X chromosomes phenotypically unaffected?
The answer to this question is that X inactivation is incomplete. Some regions of the X chromosome remain active in all copies. For example, the tips of the short and long arms of the X chromosome do not undergo inactivation. The tip of the short arm of the X chromosome is homologous to the distal short arm of the Y chromosome (see Chapter 6 ). In total, about 15% to 20% of the genes on the human X chromosome escape inactivation, and relatively more genes on the short arm escape inactivation than on the long arm. Some of the X-linked genes that remain active on both copies of the X chromosome have homologs on the Y chromosome, preserving equal gene dosage in males and females. Thus having extra (or missing) copies of active portions of the X chromosome contributes to a disease phenotype.
X inactivation is random, fixed, and incomplete. The last feature helps to explain why, despite X inactivation, most persons with abnormal numbers of sex chromosomes have a disease phenotype.
The X inactivation center contains a gene, XIST, which is transcribed only on the inactive X chromosome its 17-kb mRNA transcripts are detected in normal females but not in normal males. The RNA transcript, however, is not translated into a protein and is an example of a long noncoding RNA (lncRNA see Chapter 2 ). The XIST RNA transcript remains in the nucleus and coats the inactive X chromosome, recruiting other cellular proteins that inhibit transcription. This process acts as a signal that leads to other aspects of inactivation, including late replication and condensation of the inactive X chromosome.
Methylation and histone deacetylation are additional features of the inactive X chromosome. Many CG dinucleotides in the 5′ regions of genes on the inactive X are heavily methylated, and the administration of demethylating agents, such as 5-azacytidine, can partially reactivate an inactive X chromosome in vitro. However, methylation does not appear to be involved in spreading the inactivation signal from the inactivation center to the remainder of the X chromosome. It is more likely to be responsible for maintaining the inactivation of a specific X chromosome in a cell and all of its descendants.
The XIST gene is located in the X inactivation center and is required for X inactivation. It encodes a lncRNA product that coats the inactive X chromosome. X inactivation is also associated with methylation of the inactive X chromosome, a process that might help to ensure the long-term stability of inactivation.
Sex-linked genes are those that are located on either the X or the Y chromosome. Because only a few dozen genes are known to be located on the human Y chromosome, our attention will be focused mostly on X-linked diseases. These have traditionally been grouped into X-linked recessive and X-linked dominant categories, and these categories are used here for consistency with other literature. However, because of variable expression, incomplete penetrance, and the effects of random X inactivation, the distinction between X-linked dominant and X-linked recessive inheritance is sometimes ambiguous.
X-Linked Recessive Inheritance
A number of well-known diseases and traits are caused by X-linked recessive genes. These include hemophilia A ( Clinical Commentary 5.1 ), Duchenne muscular dystrophy ( Clinical Commentary 5.2 ), and red–green color blindness (see Box 5.1 ). Additional X-linked diseases are listed in Table 5.1 . The inheritance patterns and recurrence risks for X-linked recessive diseases differ substantially from those for diseases caused by autosomal genes.
From Hoffbrand VA. Color Atlas of Clinical Hematology. 3rd ed. Philadelphia: Mosby 2000:281-283.
Modified from McCance K, Huether S. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 5th ed. St. Louis: Mosby 2005.
Hemophilia A is caused by mutations in the gene that encodes clotting factor VIII and affects approximately 1 in 5000 to 1 in 10,000 males worldwide. It is the most common of the severe bleeding disorders and has been recognized as a familial disorder for centuries. The Talmud states that boys whose brothers or cousins bled to death during circumcision are exempt from the procedure (this may well be the first recorded example of genetic counseling).
Hemophilia A is caused by deficient or defective factor VIII, a key component of the clotting cascade. Fibrin formation is affected, resulting in prolonged and often severe bleeding from wounds and hemorrhages in the joints and muscles ( Fig. 5.3 ). Bruising is often seen. Hemarthroses (bleeding into the joints) are common in the ankles, knees, hips, and elbows. These events are often painful, and repeated episodes can lead to destruction of the synovium and diminished joint function. Intracranial hemorrhages can occur and are a leading cause of death. Platelet activity is normal in hemophiliacs, so minor lacerations and abrasions do not usually lead to excessive bleeding.
Hemophilia A varies considerably in its severity, and this variation is correlated directly with the level of factor VIII. About half of hemophilia A patients fall into the severe category, with factor VIII levels that are less than 1% of normal. These persons experience relatively frequent bleeding episodes, often several per month. Patients with moderate hemophilia (1%–5% of normal factor VIII) generally have bleeding episodes only after mild trauma and typically experience one to several episodes per year. Persons with mild hemophilia have 5% to 30% of the normal factor VIII level and usually experience bleeding episodes only after surgery or relatively severe trauma.
Historically, hemophilia A was often fatal before 20 years of age, but a major advance in treatment came in the early 1960s with the ability to purify factor VIII from donor plasma. Factor VIII is usually administered at the first sign of a bleeding episode and is a highly effective treatment. Prophylactic factor VIII administration in severe hemophiliacs is effective in preventing loss of joint function. By the 1970s, the median age at death of persons with hemophilia had increased to 68 years.
The major drawback of donor-derived factor VIII was the fact that because a typical infusion contained plasma products from hundreds or thousands of different donors, it was often contaminated by viruses. Consequently, patients often suffered from hepatitis B and C infections. Even more seriously, human immunodeficiency virus (HIV) can be transmitted in this manner, and it is estimated that half of American hemophilia patients treated with donor-derived factor VIII between 1978 and 1985 became infected with HIV. From 1979 to 1998, acquired immune deficiency syndrome (AIDS) accounted for nearly half of deaths among Americans with hemophilia A, which resulted in a decrease in the median age at death to 49 years in the 1980s. Donor blood has been screened for HIV since 1985, and heat treatment of donor-derived factor VIII kills HIV and hepatitis B virus, nearly eliminating the threat of infection. Consequently, AIDS mortality among those with hemophilia A has decreased markedly since 1995.
Identification and sequencing of the factor VIII gene has led to a number of insights. Patients with nonsense or frameshift mutations usually develop severe hemophilia, and those with missense mutations usually have mild to moderate disease. This is expected because nonsense and frameshift mutations typically produce a transcript or truncated protein that is degraded and lost. Missense mutations produce a single amino acid substitution without a dominant negative effect, usually resulting in an altered but partially functional protein product. Many of the point mutations take place at methylated CG sequences, which are hot spots for mutation (see Chapter 3 ). About 45% of severe cases of hemophilia A are caused by a chromosome inversion (see Chapter 6 ) that disrupts the factor VIII gene. An additional 5% of patients have deletions, which usually lead to relatively severe disease. About 10% of female heterozygotes have factor VIII levels less than 35%, and some of these are manifesting heterozygotes (see text), with mild symptoms of hemophilia A.
Cloning of the factor VIII gene has enabled the production of human factor VIII using recombinant DNA techniques. Extensive clinical testing showed that recombinant factor VIII works as effectively as the donor-derived form, and it was approved for commercial use in 1994. Recombinant factor VIII has the advantage that there is no possibility of viral contamination. However, as with other forms of factor VIII, recombinant factor VIII generates antifactor VIII antibody production in approximately 10% to 15% of patients. (This response is most common in patients who have no native factor VIII production.)
Two other major bleeding disorders are hemophilia B and von Willebrand disease. Hemophilia B, sometimes called Christmas disease, ∗
∗ Christmas was the last name of the first reported patient.
is also an X-linked recessive disorder and is caused by a deficiency of clotting factor IX. This condition is about one-fifth as common as hemophilia A and can be treated with donor-derived or recombinant factor IX. Von Willebrand disease is an autosomal dominant disorder that is highly variable in expression. Although it can affect as many as 1% of individuals of European descent, it reaches severe expression in fewer than 1 in 10,000. The von Willebrand factor, which is encoded by a gene on chromosome 12, acts as a carrier protein for factor VIII. In addition, it binds to platelets and to damaged blood vessel endothelium, thus promoting the adhesion of platelets to damaged vessel walls.
Hemophilia is of historical interest because it affected members of the royal families of Germany, Spain, England, and Russia ( Fig. 5.4 ). Among these families, Queen Victoria of England was the first known heterozygous hemophilia carrier. She had one affected son, and two of her daughters had affected sons, making them presumptive carriers. One of her affected great-grandsons was the Tsarevitch Alexei of Russia, the son of Tsar Nicholas II and Alexandra. Grigori Rasputin, called the “mad monk,” had an unusual ability to calm the Tsarevitch during bleeding episodes, probably through hypnosis. As a result he came to have considerable sway in the royal court, and some historians believe that his destabilizing influence helped to bring about the 1917 Bolshevik revolution. Recently, the Russian royal family was again touched by genetics. Using the polymerase chain reaction, autosomal DNA microsatellites and mitochondrial DNA sequences were assayed in the remains of several bodies exhumed near Yekaterinburg, the reputed murder site of the royal family. Analysis of this genetic variation and comparison with living maternal relatives showed that the bodies were indeed those of the Russian royal family. Further analysis demonstrated that Alexei had a pathogenic mutation in the gene that encodes factor IX, establishing that the royal families were affected by hemophilia B (rather than the more common hemophilia A).
Splotchy Cats Show Why It’s Better to Be Female
I f you’ve never really noticed the wide range of colors that can adorn the domestic cat, you might want to spend some time skimming through the official color charts of the Cat Fanciers Association website. According to the association, which claims to maintain the largest registry of pedigreed cats, cats can come in seal lynx and mackerel tabby, chinchilla silver and cream smoke, blue-patched and blue point. There are mitted cats and van cats, as well as more obvious cats that you might actually be able to picture in your mind, like “green-eyed white.” (Here is a very detailed poster showing much of the complexity in distinguishing breeds.)
This Crayola box of fur is enabled by just a handful of genes, leveraged by a long history of human breeders obsessed with getting the rarest or most beautiful or most striking combinations. But in that world of cat possibility, perhaps the strangest and most interesting of all is the common calico cat. All calicos (and all tortoiseshells) have blotches of black and orange fur. They are also almost always female. The reason why has to do with a genetic phenomenon that gets down to the very roots of what it means to be female.
It was only a bit more than a hundred years ago that biologists realized that male and female mammals actually were different in the structure of their chromosomes, the packages that house their DNA, with females having two X chromosomes and males having an X and a Y. But the strange thing was that the human body worked perfectly well either way. Normally, variation in the number of chromosomes causes significant genetic disease for example, people with extra copy of chromosome 21 have Down syndrome, which usually comes with developmental and cognitive problems. Since females have twice as many X-chromosome genes, they should have twice the appropriate amount of proteins coded by those genes, leading to a lot of biological errors. Yet they are healthy. In women, there evidently was some trick that offset the doubling of the X chromosome, but it was a mystery.
In 1959 a researcher noticed that in cells from female mammals, one of the two X chromosomes looked funny during the resting period of the cell cycle it shriveled up into a blob and clung to the outer edge of the cell nucleus. For genes to be transcribed, a chromosome must loosen up its structure so that its DNA can be physically accessed by the transcription machinery. These chromosomes, one inside each cell, looked like they couldn’t possibly be doing anything.
Two years later, the British geneticist Mary Lyon had the idea that what he was looking at was also the way that female cells compensate for having twice as much X. She proposed that each cell randomly and permanently deactivates one of its X chromosomes, disabling one of them and preventing the cell from being swamped with protein. She was right, and the discovery of X-inactivation (now sometimes called lyonization) was the first description of an epigenetic phenomenon—the realization that gene activity can be permanently changed by something other than heritable changes to DNA.
Each calico is both an orange cat and a black cat, and there will never again be one like her. “Identical” twins don’t even have the same patches, because chance dictates which X-chromosomes are inactivated.
Since then, more details have been worked out: When an egg (which has just one X chromosome) first meets and unites with a sperm cell that has an X chromosome (one half of sperm cells have Xs and lead to girls half have Ys and lead to boys), both X chromosomes are active. The fertilized egg grows and divides into a ball of hundreds of cells, still with both X’s active. Then after a little more than a week, a gene called XIST (X-inactive specific transcript) springs into action, producing an RNA that tightly binds one of the two chromosomes, wrapping it up so snugly as to prevent almost all its genes from being transcribed. The silenced X chromosome will stay that way throughout the life of the cell. Each time it divides, its daughter cells will maintain the same pattern of inactivation.
The system works the same in all female placental mammals. (Marsupials have their own weird system for doing the same thing.) But in calico and tortoiseshell cats, it becomes gloriously visible.
On the X chromosome of cats is a skin- and fur-color gene that has two variations (alleles) that dictate either orange fur or black fur. If a female cat inherits one X chromosome with the black allele and one with the orange version, each cell will have both versions, but X-inactivation means that some of her skin cells will code for orange and some for black. The inactivation happens very early in development, when the cat-in-the-making is still just a ball of cells, and the particular nature of skin tissue is that cells and their progeny stay close together. One of those primordial skin progenitor cells that happens to have an active orange allele will give rise to a cohesive blob of millions of cells in the fully developed cat, forming a big orange blotch. The same is true for those coding for black. (Tortoiseshells are completely black and orange, but calicos have white on their bellies, chests, and legs due to an another gene that causes piebalding—areas without any pigment in the skin and fur at all.)
The pattern is random, so that no two calicos or tortoiseshells are alike. Each is both an orange cat and a black cat, and there will never again be one like her. Identical twins don’t even have the same patches, because chance dictates which X-chromosomes are inactivated, and therefore which cells carry the orange trait and which ones code for black. The first cat to be cloned was a calico whose clone looked very different from her. A cell from Rainbow the calico became CC, who is dark gray (“blue,” in the official CFA terminology) and white. (Rainbow was a less common type of calico, in which the dark patches are not pure black but dark tabby gray, a pattern sometimes called caliby.) The implication: The cell that led to CC was one in which the black allele was active and the orange inactive.
The small cat in the right picture is CC (“carbon copy”), the first-ever cloned cat. The cat in the left picture is her biological mother, Rainbow, who passed CC one cell in which the allele for black fur was active and the orange allele was inactive. Taeyoung Shin et al. / Nature
X-inactivation plays out differently in other parts of the body, so that some tissues have big patches with only maternal X or paternal X, and other tissues include each sprinkled in with the other. In a 2014 study with mice , Jeremy Nathans of Johns Hopkins University labeled Xs in either red or green depending on which of the two chromosomes was active. The result was stunning diversity of patterns: big patches of red and green in the intestinal lining, streaks in the smooth muscle of the gut, tiny stipples in the brain. As to what consequences there might be for the creature as a whole, there are as yet few answers.
In these images from female mice, the cells with active X chromosomes from one parent are labeled green, while those from the other parent are labeled red. The colors are arranged differently in the various images, depending on how each organ grows and develops. Hao Wu et al. / Neuron
In general, the phenomenon of X-inactivation has been underappreciated and understudied, says Barbara Migeon, a professor at the Johns Hopkins Institute of Genetic Medicine. When Mary Lyon first proposed the idea of X-inactivation, Migeon was just beginning her fellowship in genetics, and she got hooked. “I was in the right place at the right time,” she says now. Ever since then, she has studied its mechanisms and consequences, and it has lead her to propose a theory: X-inactivation gives women an inherent genetic advantage.
The idea is basically that female mammals simply have more options, because the cells in their bodies are more diverse: They have two different X chromosomes with two different sets of gene variants. That greater range of possibility allows females to survive diseases that cripple or kill males, an effect that she explores in her 2007 book, Females are Mosaics . “We have an advantage in health as well as disease,” she says. “It’s the fact that we have heterogeneity for a lot of proteins, and can make new proteins that males don’t make.”
The female genetic advantage is obvious in the case of X-linked diseases, which are caused by a mutation on the X chromosome. Since males have only one X chromosome, if they have a mutation there, they have only that one mutated copy. With no good version to fall back upon, they get very sick or die. But women almost always have another copy of the gene that is normal and can compensate. With this backup system, they stay relatively healthy, or sometimes have no symptoms at all. Migeon puts it this way: A female is a composite of two intermingled cell populations that share gene products with one another. The result is an organism that is inherently more resilient.
One example is Fabry disease , a rare condition caused by a mutation in the GLA gene that disrupts the production of an enzyme called alpha-galactosidase A. Without functional enzymes, a type of fat accumulates in cells all over the body, leading to cataracts, strokes, kidney failure, and other serious symptoms.
A woman who inherits the mutation usually only has one bad copy the good gene on her other X rescues her from that fate. Even though just half her cells produce functional protein, they share it with the sick cells or simply take over their job. A woman with a GLA mutation usually will have milder symptoms or symptoms that begin late in life. (Incidentally, this is also what maintains the mutation in the species: Women live long enough to pass the gene on to the next generation.) Duchenne muscular dystrophy works much the same way—with rare exceptions, only boys are affected, due to a mutation of a gene on the X chromosome.
Males die at higher rates than women at every age, from birth to old age—and even in utero and among infants. X-inactivation could be the reason.
Some X-linked genetic disorders are so severe that only women have them, because only they can survive long enough males with the same mutation die before they are born or shortly after birth. Rett syndrome, which causes autism-like symptoms, is one of them. Incontinentia pigmenti, a mutation in the IKBKG gene that causes problems with the skin, eyes, and teeth, is also almost completely a female disease.
Migeon points out that men die at higher rates than women at every age, from birth to old age, a disparity that’s usually chalked up to male hormones, larger body size, or risk-taking behavior. But the survival disadvantage for men occurs even in utero and among infants, when these factors have little or no effect. X-inactivation could be the reason.
She proposes that the X effect goes beyond protection from disease Migeon thinks that women likely have other biological advantages as well. If 20 percent of the roughly 1,100 genes of the two X chromosomes are functionally different from one another, on average, that potentially provides women with a whole new set of molecules and new cellular functions.
In the brain, for example, it’s entirely possible that this genetic diversity could give rise to cells that have slightly different capabilities, leading to networks that enable a broader range of responses or even new ways to process information. X-chromosome inactivation “may represent one of the more significant mechanisms by which individual differences in [brain] function are generated,” writes Nathans in the conclusion of his study on how X-inactivation manifested in different parts of the mouse body. Migeon puts it a different way. “We want to be equal to men, but we really are better,“ she quips.
So far, the evidence doesn’t quite prove that. But the study of the effects of X-inactivation is relatively new, and it’s plausible that having a broader repertoire of genes can confer a variety of as-yet-unknown biological advantages. Among New World monkeys, for example, X-inactivation enhances vision in females. The gene that controls the pigments in the monkey eye that make it possible to distinguish between different wavelengths of light is located on the X chromosome. In New World monkeys the gene has three alleles, meaning that while males can only have two of the three alleles and are restricted to dichromatic color vision, some female monkeys carry all three. Their world, like ours, is one of brilliant hues.
Kat McGowan is a contributing editor at Discover magazine and an independent journalist based in Berkeley, Calif., and New York City.
Each child of a mother affected with an X-linked dominant trait has a 50% chance of inheriting the mutation and thus being affected with the disorder. If only the father is affected, 100% of the daughters will be affected, since they inherit their father's X chromosome, and 0% of the sons will be affected, since they inherit their father's Y chromosome.
There are less X-linked dominant conditions than X-linked recessive, because dominance in X-linkage requires the condition to present in females with only a fraction of the reduction in gene expression of autosomal dominance, since roughly half (or as many as 90% in some cases) of a particular parent's X chromosomes are inactivated in females.
Females possessing one X-linked recessive mutation are considered carriers and will generally not manifest clinical symptoms of the disorder, although differences in X chromosome inactivation can lead to varying degrees of clinical expression in carrier females since some cells will express one X allele and some will express the other. All males possessing an X-linked recessive mutation will be affected, since males have only a single X chromosome and therefore have only one copy of X-linked genes. All offspring of a carrier female have a 50% chance of inheriting the mutation if the father does not carry the recessive allele. All female children of an affected father will be carriers (assuming the mother is not affected or a carrier), as daughters possess their father's X chromosome. If the mother is not a carrier, no male children of an affected father will be affected, as males only inherit their father's Y chromosome.
The incidence of X-linked recessive conditions in females is the square of that in males: for example, if 1 in 20 males in a human population are red–green color blind, then 1 in 400 females in the population are expected to be color-blind ( 1 /20)*( 1 /20).
- eyes in Drosophila melanogaster flies was one of the earliest sex-linked genes discovered. 
- Fur color in domestic cats: the gene that causes orange pigment is on the X chromosome thus a Calico or tortoiseshell cat, with both black (or gray) and orange pigment, is nearly always female.
- The first sex-linked gene ever discovered was the "lacticolor" X-linked recessive gene in the moth Abraxas grossulariata by Leonard Doncaster. 
It is important to distinguish between sex-linked characters, which are controlled by genes on sex chromosomes, and two other categories. 
Sex-influenced traits Edit
Sex-influenced or sex-conditioned traits are phenotypes affected by whether they appear in a male or female body.  Even in a homozygous dominant or recessive female the condition may not be expressed fully. Example: baldness in humans.
Sex-limited traits Edit
These are characters only expressed in one sex. They may be caused by genes on either autosomal or sex chromosomes.  Examples: female sterility in Drosophila and many polymorphic characters in insects, especially in relation to mimicry. Closely linked genes on autosomes called "supergenes" are often responsible for the latter.   
Neuroimaging Part II
Hisham M. Dahmoush , . Arastoo Vossough , in Handbook of Clinical Neurology , 2016
Kallmann syndrome is a genetic disorder which is inherited as an X-linked (most commonly KAL1 gene mutation) or autosomal-dominant (FGFR1 gene mutation) disease, though a large number of associated genes have been identified ( Dode et al., 2003 Sato et al., 2004 ). Hypogonadotropic hypogonadism and anosmia-hyposmia are the main features of the syndrome. The hypogonadism is due to failure of migration of gonadotropin-releasing hormone 1 neurons from the olfactory placode to the forebrain ( Teixeira et al., 2010 ), while the olfactory disturbance is due to failure of migration of cells from the olfactory placode to the telencephalon, resulting in aplasia or hypoplasia of the olfactory bulbs and tracts ( Truwit et al., 1993 ). Luteinizing hormone and follicle-stimulating hormone are typically low. On MRI, the adenohypophysis is either normal in size or small (due to decreased pituitary stimulation). The olfactory bulbs are absent either bilaterally or unilaterally, and the olfactory sulci are either not formed or shallow ( Yousem et al., 1996 ). The absence of the olfactory sulcus results in the imaging finding of fused appearance of the gyrus rectus with the medial orbital frontal gyrus ( Fig. 63.26 ). Associated renal anomalies can be present ( Zenteno et al., 1999 ).
Fig. 63.26 . Kallmann syndrome in a teenage male with hypogonadotropic hypogonadism and anosmia. Coronal T2-weighted imaging shows absence of the olfactory bulbs along cerebrospinal fluid-filled olfactory grooves (arrows). There is also absence of the olfactory sulcus in the medial frontal lobes resulting in a fused olfactory gyrus and medial orbital frontal gyrus.
Kashtan CE, Ding J, Garosi G, Heidet L, Massella L, Nakanishi K, Nozu K, Renieri A, Rheault M, Wang F, Gross O (2018) Alport syndrome: a unified classification of genetic disorders of collagen IV alpha345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int 93:1045–1051
Levy M, Feingold J (2000) Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 58:925–943
Savige J (2014) Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. J Physiol 592:4013–4023
Miner JH, Baigent C, Flinter F, Gross O, Judge P, Kashtan CE, Lagas S, Savige J, Blatt D, Ding J, Gale DP, Midgley JP, Povey S, Prunotto M, Renault D, Skelding J, Turner AN, Gear S (2014) The 2014 International Workshop on Alport Syndrome. Kidney Int 86:679–684
Izzedine H, Tankere F, Launay-Vacher V, Deray G (2004) Ear and kidney syndromes: molecular versus clinical approach. Kidney Int 65:369–385
Byrne MC, Budisavljevic MN, Fan Z, Self SE, Ploth DW (2002) Renal transplant in patients with Alport’s syndrome. Am J Kidney Dis 39:769–775
Perrin D, Jungers P, Grunfeld JP, Delons S, Noel LH, Zenatti C (1980) Perimacular changes in Alport’s syndrome. Clin Nephrol 13:163–167
Shah SN, Weinberg DV (2010) Giant macular hole in Alport syndrome. Ophthalmic Genet 31:94–97
Hasstedt SJ, Atkin CL (1983) X-linked inheritance of Alport syndrome: family P revisited. Am J Hum Genet 35:1241–1251
Kashtan CE, Michael AF (1996) Alport syndrome. Kidney Int 50:1445–1463
Heiskari N, Zhang X, Zhou J, Leinonen A, Barker D, Gregory M, Atkin CL, Netzer KO, Weber M, Reeders S, Gronhagen-Riska C, Neumann HP, Trembath R, Tryggvason K (1996) Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome. J Am Soc Nephrol 7:702–709
Tryggvason K, Zhou J, Hostikka SL, Shows TB (1993) Molecular genetics of Alport syndrome. Kidney Int 43:38–44
Kashtan CE (1998) Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 9:1736–1750
Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG (2003) Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 348:2543–2556
Torra R, Tazon-Vega B, Ars E, Ballarin J (2004) Collagen type IV (alpha3-alpha4) nephropathy: from isolated haematuria to renal failure. Nephrol Dial Transplant 19:2429–2432
Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K (1990) Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248:1224–1227
Antignac C, Knebelmann B, Drouot L, Gros F, Deschenes G, Hors-Cayla MC, Zhou J, Tryggvason K, Grunfeld JP, Broyer M (1994) Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression. J Clin Invest 93:1195–1207
Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G, Clementi M, La Manna A, Miglietti N, Mancini R, Mandrile G, Ghiggeri GM, Piaggio G, Brancati F, Diano L, Frate E, Pinciaroli AR, Giani M, Castorina P, Bresin E, Giachino D, De Marchi M, Mari F, Bruttini M, Renieri A, Ariani F (2014) Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet 86:252–257
Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, Bole-Feysot C, Pruvost S, Nitschke P, Plaisier E, Knebelmann B, Macher MA, Noel LH, Gubler MC, Antignac C, Heidet L (2014) Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol 25:2740–2751
van der Loop FT, Heidet L, Timmer ED, van den Bosch BJ, Leinonen A, Antignac C, Jefferson JA, Maxwell AP, Monnens LA, Schroder CH, Smeets HJ (2000) Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int 58:1870–1875
Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61:1947–1956
Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano R, Seri M, Miglietti N, Bresin E, Renieri A (2004) Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 65:1598–1603
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, Miglietti N, Antonucci MF, Cetta F, Sayer JA, van den Wijngaard A, Yau S, Mari F, Bruttini M, Ariani F, Dahan K, Smeets B, Antignac C, Flinter F, Renieri A (2015) Evidence of digenic inheritance in Alport syndrome. J Med Genet 52:163–174
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2000) X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 11:649–657
Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, Schrier RW (2010) Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 21:876–883
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC (2003) X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol 14:2603–2610
Rheault MN, Kren SM, Hartich LA, Wall M, Thomas W, Mesa HA, Avner P, Lees GE, Kashtan CE, Segal Y (2010) X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome. Nephrol Dial Transplant 25:764–769
Nakanishi K, Iijima K, Kuroda N, Inoue Y, Sado Y, Nakamura H, Yoshikawa N (1998) Comparison of alpha5(IV) collagen chain expression in skin with disease severity in women with X-linked Alport syndrome. J Am Soc Nephrol 9:1433–1440
Vetrie D, Flinter F, Bobrow M, Harris A (1992) X inactivation patterns in females with Alport’s syndrome: a means of selecting against a deleterious gene? J Med Genet 29:663–666
Gale RE, Wheadon H, Boulos P, Linch DC (1994) Tissue specificity of X-chromosome inactivation patterns. Blood 83:2899–2905
Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M, Gauthier L, Fleharty M, Kirby A, Cummings BB, Castel SE, Karczewski KJ, Aguet F, Byrnes A, GTEx Consortium Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group Statistical Methods groups—Analysis Working Group Enhancing GTEx (eGTEx) groups NIH Common Fund NIH/NCI NIH/NHGRI NIH/NIMH NIH/NIDA Biospecimen Collection Source Site—NDRI Biospecimen Collection Source Site—RPCI Biospecimen Core Resource—VARI Brain Bank Repository—University of Miami Brain Endowment Bank Leidos Biomedical—Project Management ELSI Study Genome Browser Data Integration &Visualization—EBI Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Lappalainen T, Regev A, Ardlie KG, Hacohen N, MacArthur DG (2017) Landscape of X chromosome inactivation across human tissues. Nature 550:244–248
Lemmink HH, Mochizuki T, van den Heuvel LP, Schroder CH, Barrientos A, Monnens LA, van Oost BA, Brunner HG, Reeders ST, Smeets HJ (1994) Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3:1269–1273
Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, Verellen-Dumoulin C, Chan B, Schroder CH, Smeets HJ, Reeders ST (1994) Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8:77–81
Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA (2013) COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. J Am Soc Nephrol 24:1945–1954
Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K (2014) Natural history of genetically proven autosomal recessive Alport syndrome. Pediatr Nephrol 29:1535–1544
Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12:97–106
Longo I, Scala E, Mari F, Caselli R, Pescucci C, Mencarelli MA, Speciale C, Giani M, Bresin E, Caringella DA, Borochowitz ZU, Siriwardena K, Winship I, Renieri A, Meloni I (2006) Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families. Nephrol Dial Transplant 21:665–671
Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Muller GA, Gross O (2012) Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int 81:779–783
Pochet JM, Bobrie G, Landais P, Goldfarb B, Grunfeld JP (1989) Renal prognosis in Alport’s and related syndromes: influence of the mode of inheritance. Nephrol Dial Transplant 4:1016–1021
Colville D, Wang YY, Jamieson R, Collins F, Hood J, Savige J (2000) Absence of ocular manifestations in autosomal dominant Alport syndrome associated with haematological abnormalties. Ophthalmic Genet 21:217–225
Rosado C, Bueno E, Felipe C, Valverde S, Gonzalez-Sarmiento R (2015) Study of the true clinical progression of autosomal dominant Alport syndrome in a European population. Kidney Blood Press Res 40:435–442
Benonisdottir S, Kristjansson RP, Oddsson A, Steinthorsdottir V, Mikaelsdottir E, Kehr B, Jensson BO, Arnadottir GA, Sulem G, Sveinbjornsson G, Kristmundsdottir S, Ivarsdottir EV, Tragante V, Gunnarsson B, Runolfsdottir HL, Arthur JG, Deaton AM, Eyjolfsson GI, Davidsson OB, Asselbergs FW, Hreidarsson AB, Rafnar T, Thorleifsson G, Edvardsson V, Sigurdsson G, Helgadottir A, Halldorsson BV, Masson G, Holm H, Onundarson PT, Indridason OS, Benediktsson R, Palsson R, Gudbjartsson DF, Olafsson I, Thorsteinsdottir U, Sulem P, Stefansson K (2019) Sequence variants associating with urinary biomarkers. Hum Mol Genet 28:1199–1211
Salem RM, Todd JN, Sandholm N, Cole JB, Chen WM, Andrews D, Pezzolesi MG, McKeigue PM, Hiraki LT, Qiu C, Nair V, Di Liao C, Cao JJ, Valo E, Onengut-Gumuscu S, Smiles AM, McGurnaghan SJ, Haukka JK, Harjutsalo V, Brennan EP, van Zuydam N, Ahlqvist E, Doyle R, Ahluwalia TS, Lajer M, Hughes MF, Park J, Skupien J, Spiliopoulou A, Liu A, Menon R, Boustany-Kari CM, Kang HM, Nelson RG, Klein R, Klein BE, Lee KE, Gao X, Mauer M, Maestroni S, Caramori ML, de Boer IH, Miller RG, Guo J, Boright AP, Tregouet D, Gyorgy B, Snell-Bergeon JK, Maahs DM, Bull SB, Canty AJ, Palmer CNA, Stechemesser L, Paulweber B, Weitgasser R, Sokolovska J, Rovite V, Pirags V, Prakapiene E, Radzeviciene L, Verkauskiene R, Panduru NM, Groop LC, McCarthy MI, Gu HF, Mollsten A, Falhammar H, Brismar K, Martin F, Rossing P, Costacou T, Zerbini G, Marre M, Hadjadj S, McKnight AJ, Forsblom C, McKay G, Godson C, Maxwell AP, Kretzler M, Susztak K, Colhoun HM, Krolewski A, Paterson AD, Groop PH, Rich SS, Hirschhorn JN, Florez JC, SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium (2019) Genome-wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen. J Am Soc Nephrol 30:2000–2016. https://doi.org/10.1681/ASN.2019030218
Haas ME, Aragam KG, Emdin CA, Bick AG, International Consortium for Blood P, Hemani G, Davey Smith G, Kathiresan S (2018) Genetic association of albuminuria with cardiometabolic disease and blood pressure. Am J Hum Genet 103:461–473
Sinnott-Armstrong N, Tanigawa Y, Amar D, Mars NJ, Aguirre M, Venkataraman GR, Wainberg M, Ollila HM, Pirruccello JP, Qian J, Shcherbina A, FinnGen, Rodriguez F, Assimes TL, Agarwala V, Tibshirani R, Hastie T, Ripatti S, Pritchard JK, Daly J, Rivas MA (2019) Genetics of 38 blood and urine biomarkers in the UK Biobank. bioRxiv preprint. https://doi.org/10.1101/660506
Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, Gagliano Taliun SA, et al. (2019) Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. bioRxiv preprint. https://doi.org/10.1101/563866
Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, Cortes A, Welsh S, Young A, Effingham M, McVean G, Leslie S, Allen N, Donnelly P, Marchini J (2018) The UK Biobank resource with deep phenotyping and genomic data. Nature 562:203–209
Dagher H, Yan Wang Y, Fassett R, Savige J (2002) Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome. Hum Mutat 20:321–322
Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, Venkat-Raman G, Ennis S (2016) Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 31:961–970
Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso AS, Jiang R, Lindsey TB, Wu G, Sparks MA, Smith SR, Webb NJ, Kalra PA, Adeyemo AA, Shaw AS, Conlon PJ, Jennette JC, Howell DN, Winn MP, Gbadegesin RA (2014) Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int 86:1253–1259
Zanetti D, Rao A, Gustafsson S, Assimes TL, Montgomery SB, Ingelsson E (2019) Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion. Kidney Int 95:1197–1208
Schurz H, Muller SJ, van Helden PD, Tromp G, Hoal EG, Kinnear CJ, Moller M (2019) Evaluating the accuracy of imputation methods in a five-way admixed population. Front Genet 10:34
Wright CF, West B, Tuke M, Jones SE, Patel K, Laver TW, Beaumont RN, Tyrrell J, Wood AR, Frayling TM, Hattersley AT, Weedon MN (2019) Assessing the pathogenicity, penetrance, and expressivity of putative disease-causing variants in a population setting. Am J Hum Genet 104:275–286
Chatterjee R, Hoffman M, Cliften P, Seshan S, Liapis H, Jain S (2013) Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria. PLoS One 8:e76360
Wang YF, Ding J, Wang F, Bu DF (2004) Effect of glycine substitutions on alpha5(IV) chain structure and structure-phenotype correlations in Alport syndrome. Biochem Biophys Res Commun 316:1143–1149
X-linked female-biased genes accurately predict sex and suggest tissue-specific candidates for escape from X-chromosome inactivation
We accurately predicted sex from gene expression, as previously explored (17), using X-linked genes (9) (fig. S4, A to D) with gradient boosted trees. Although the most predictive X-linked genes (fig. S4E) are those known to escape XCI, we identified 40 X-linked female-biased genes predictive of sex (within the top tertile with respect to their Shapley values) not previously described as XCI escapees (table S3). These results suggest further evaluation of these genes as potential XCI escapees we did not directly test escape from XCI, and female-biased expression of X-linked genes may originate from other mechanisms. Sex prediction from autosomal genes was less accurate (mean accuracy = 84%), less specific (mean specificity = 56%, sensitivity = 96% fig. S4D), and required more genes (fig. S4F) than prediction based on X-linked genes. However, in two tissues—breast and muscle—autosomal genes predicted sex with specificity ≥ 90% and sensitivity ≥ 98% (fig. S4G).
Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).
Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
Manolio, T.A. Genomewide association studies and assessment of the risk of disease. N. Engl. J. Med. 363, 166–176 (2010).
Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).
Visscher, P.M. et al. Genome partitioning of genetic variation for height from 11,214 sibling pairs. Am. J. Hum. Genet. 81, 1104–1110 (2007).
Rimm, E.B. et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 338, 464–468 (1991).
Colditz, G.A. & Hankinson, S.E. The Nurses' Health Study: lifestyle and health among women. Nat. Rev. Cancer 5, 388–396 (2005).
Psaty, B.M. et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ. Cardiovasc. Genet. 2, 73–80 (2009).
Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
Visscher, P.M., Yang, J. & Goddard, M.E. A commentary on 'common SNPs explain a large proportion of the heritability for human height' by Yang et al. (2010). Twin Res. Hum. Genet. 13, 517–524 (2010).
Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).
Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).
Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).
Speliotes, E.K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).
Smith, N.L. et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) consortium. Circulation 121, 1382–1392 (2010).
Shah, S.H. & Pitt, G.S. Genetics of cardiac repolarization. Nat. Genet. 41, 388–389 (2009).
Preston, A.E. & Barr, A. The plasma concentration of factor viii in the normal population. II. The effects of age, sex and blood group. Br. J. Haematol. 10, 238–245 (1964).
O'Donnell, J., Boulton, F.E., Manning, R.A. & Laffan, M.A. Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels. Arterioscler. Thromb. Vasc. Biol. 22, 335–341 (2002).
Liu, J.Z. et al. A versatile gene-based test for genome-wide association studies. Am. J. Hum. Genet. 87, 139–145 (2010).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Price, A.L., Zaitlen, N.A., Reich, D. & Patterson, N. New approaches to population stratification in genome-wide association studies. Nat. Rev. Genet. 11, 459–463 (2010).
Bulmer, M.G. The Mathematical Theory of Quantitative Genetics (Oxford University Press, New York, New York, USA, 1985).
Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).
Purcell, S.M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).
Magnusson, P.K. & Rasmussen, F. Familial resemblance of body mass index and familial risk of high and low body mass index. A study of young men in Sweden. Int. J. Obes. Relat. Metab. Disord. 26, 1225–1231 (2002).
Schousboe, K. et al. Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries. Twin Res. 6, 409–421 (2003).
Eyre-Walker, A. Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc. Natl. Acad. Sci. USA 107, 1752–1756 (2010).
The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Dickson, S.P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D.B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010).
McClellan, J. & King, M.-C. Genetic heterogeneity in human disease. Cell 141, 210–217 (2010).
Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
Visscher, P.M., Hill, W.G. & Wray, N.R. Heritability in the genomics era-concepts and misconceptions. Nat. Rev. Genet. 9, 255–266 (2008).
Orstavik, K.H. et al. Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level. Am. J. Hum. Genet. 37, 89–101 (1985).
de Lange, M., Snieder, H., Ariens, R.A., Spector, T.D. & Grant, P.J. The genetics of haemostasis: a twin study. Lancet 357, 101–105 (2001).
Dalageorgou, C. et al. Heritability of QT interval: how much is explained by genes for resting heart rate? J. Cardiovasc. Electrophysiol. 19, 386–391 (2008).
Russell, M.W., Law, I., Sholinsky, P. & Fabsitz, R.R. Heritability of ECG measurements in adult male twins. J. Electrocardiol. 30 Suppl, 64–68 (1998).
Qi, L. et al. Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum. Mol. Genet. 19, 2706–2715 (2010).
Cornelis, M.C. et al. The gene, environment association studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet. Epidemiol. 34, 364–372 (2010).
Laurie, C.C. et al. Quality control and quality assurance in genotypic data for genome-wide association studies. Genet. Epidemiol. 34, 591–602 (2010).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Kent, J.W. Jr. Dyer, T.D. & Blangero, J. Estimating the additive genetic effect of the X chromosome. Genet. Epidemiol. 29, 377–388 (2005).
Zhang, Z. et al. Mixed linear model approach adapted for genome-wide association studies. Nat. Genet. 42, 355–360 (2010).
Kang, H.M. et al. Variance component model to account for sample structure in genome-wide association studies. Nat. Genet. 42, 348–354 (2010).
Simpson JL: Genetic programming in ovarian development and oogenesis. In Lobo RA, Kelsey JMR (eds): Menopause Biology and Pathobiology. pp 77, 94. London, Academic Press, 2000
Simpson JL, Rajkovic A: Ovarian differentiation and gonadal failure. Am J Med Genet 89:186, 1999
Simpson JL, Elias S: Genetics in Obstetrics and Gynecology. 3rd ed.. Philadelphia, W.B. Saunders, 2002, p. 270.
Simpson, J.L.: Disorders of abnormal sexual differentiation. (In) Clinical Pediatric and Adolescent Gynecology (J.S. Sanfilippo, E. Lara-Torre, K. Edmonds, C. Templeman, eds). Informa Healthcare, New York, NY, 2009.
Simpson, JL: Mammalian Sex Determination, (In) Encyclopedia of Life Sciences,John Wiley & Sons, Ltd. published online, March 2008. doi: 10.1005/9780470015902. a0001886.pub2
Simpson, JL. Disorders of the gonads, genital tract and genitalia (In) Principles and Practice of Medical Genetics, 6th ed. (Rimoin DL, Connor Jm, Pyertiz RE, Korf BR eds.), New York, Churchill-Livingstone, 2012, in press
Simpson JL. Genetics of Female Fertility: X Chromosome Disorders. (In) Methods of Molecular Biology- Human Fertility (Wasserman P, Rosenwaks Z, eds.). Humana Press, New York. In press.
Patsavoudi E, Magre S, Castanier M et al: Dissociation between testicular morphogenesis and functional differentiation ofLeydig cells. J Endocrinol. 1985 May105(2):235-8.
Magre S, Jost A: Dissociation between testicular organogenesis and endocrine cytodifferentiationof Sertoli cells. Proc Natl Acad Sci U S A. 1984 Dec81(24):7831-4.
Behringer RR, Cate RL, Froelick GJ et al: Abnormal sexual development in transgenic mice chronically expressing mullerianinhibiting substance. Nature. 1990 May 10345(6271):167-70.
Jost A (1953) Problems of fetal endocrinology. The gonadal and hypophyseal hormones. Recent Prog Horm Res 8:379-418.
Jost A: Problems of fetal endocrinology: the adrenal glands. Recent Prog Horm Res. 196622:541-74.
Abir R, Fisch B, Nitke S, et al: Morphological study of fully and partially isolated early human follicles. Fertil Steril 75:141, 2001
Schlessinger D, Garcia-Ortiz JE, Forabosco A et al: Determination and stability of gonadal sex. J Androl. 2010 Jan-Feb31(1):16-25. Epub 2009 Oct 29.
Uhlenhaut NH, Jakob S, Anlag K et al: Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell. 2009 Dec 11139(6):1130-42.
Simpson JL: Gonadal dysgenesis and abnormalities of the human sex chromosomes: Current status of phenotypic-karyotypic correlations. Birth Defects Orig Artic Ser 11(4):23, 1975
Mathur A, Stekol L, Schatz D, et al: The parental origin of the single X chromosome in Turner syndrome: Lack of correlation with parental age or clinical phenotype. Am J Hum Genet 48:682, 1991
Cockwell A, MacKenzie M, Youings S, et al: A cytogenetic and molecular study of a series of 45,X fetuses and their parents. J Med Genet 28:152, 1991
Willard HF: The sex chromosomes and X chromosome inactivation. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Bases of Inherited Disease. pp 1191, 1211 Vol 8:New York, McGraw-Hill, 2001
Hovatta O: Pregnancies in women with Turner’s syndrome. Ann Med 31:106, 1999
Magee AC, Nevin NC, Armstrong MJ, et al: Ullrich-Turner syndrome: Seven pregnancies in an apparent 45,X woman. Am J Med Genet 75:1, 1998
Check JH, Nowroozi K, Chase JS, et al: Ovulation induction and pregnancies in 100 consecutive women with hypergonadotropic amenorrhea. Fertil Steril 53:811, 1990
Foudila T, Soderstrom-Anttila V, Hovatta O: Turner’s syndrome and pregnancies after oocyte donation. Hum Reprod 14:532, 1999
Khastgir G, Abdalla H, Thomas A, et al: Oocyte donation in Turner’s syndrome: An analysis of the factors affecting the outcome. Hum Reprod 12:279, 1997
Tarani L, Lampariello S, Raguso G, et al: Pregnancy in patients with Turner’s syndrome: Six new cases and review of literature. Gynecol Endocrinol 12:83, 1998
Dewhurst J: Fertility in 47,XXX and 45,X patients. J Med Genet 15:132, 1978
Simpson JL: Pregnancies in women with chromosomal abnormalities. In In Schulman JD, Simpson JL (eds): Genetic Diseases in Pregnancy. pp 439, 471 New York, Academic Press, 1981
Brook CG, Murset G, Zachmann M, et al: Growth in children with 45,XO Turner’s syndrome. Arch Dis Child 49:789, 1974
Ranke MB, Pfluger H, Rosendahl W, et al: Turner syndrome: Spontaneous growth in 150 cases and review of the literature. Eur J Pediatr 141:81, 1983
Tanner JM, Goldstein H, Whitehouse RH: Standards for children’s height at ages 2𠄹 years allowing for heights of parents. Arch Dis Child 45:755, 1970
Brook CG, Gasser T, Werder EA, et al: Height correlations between parents and mature offspring in normal subjects and in subjects with Turner’s and Klinefelter’s and other syndromes. Ann Hum Biol 4:17, 1977
Ranke MB, Blum WF, Haug F, et al: Growth hormone, somatomedin levels and growth regulation in Turner’s syndrome. Acta Endocrinol 116:305, 1987
Rosenfeld RG, Grumbach MM: Turner Syndrome. New York, Marcel Dekker, 1990
Rosenfeld RG, Frane J, Attie KM, et al: Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. J Pediatr 121:49, 1992
Rosenfeld RG, Attie KM, Frane J, et al: Growth hormone therapy of Turner’s syndrome: beneficial effect on adult height. J Pediatr 132:319, 1998
Grumbach MM, Conte FA: Disorders of sex differentiation. In Wilson JD, Foster DW, Kronenberg H (eds): Williams Textbook of Endocrinology. pp. 1303, Vol. 9:Philadelphia, WB Saunders, 1998
Saenger P: Turner’s syndrome. N Engl J Med 335:1749, 1996
Filippson R, Lindsten J, Almqvist S: Time of eruption of the permanent teeth, cephalometric and tooth measurement and sulphationfactor activity in 45 patients with Turner’s syndrome with different types of X chromosome aberration. Acta Endocrinol 48:91, 1965
Lindsten J, Fraccaro M: Turner’s syndrome. In Rashad MN, Mortion WRM (eds): Genital Anomalies,. pp 396, Springfield, Charles C. Thomas Publishers, 1969
Ross JL, Roeltgen D, Kushner H, et al: The Turner syndrome-associated neurocognitive phenotype maps todistal Xp. Am J Hum Genet 67:672, 2000
McCauley E, Sybert VP, Ehrhardt AA: Psychosocial adjustment of adult women with Turner syndrome. Clin Genet 29:284, 1986
McCauley E, Kay T, Ito J, et al: The Turner syndrome: Cognitive deficits, affective discrimination, and behavior problems. Child Dev 58:464, 1987
Skuse DH, James RS, Bishop DV, et al: Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387:705, 1997
Zinn AR, Tonk VS, Chen Z, et al: Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1 Am J Hum Genet 63:1757, 1998
Zinn AR, Ross JL: Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF). Semin Reprod Med 19:141, 2001
Boucher CA, Sargent CA, Ogata T, et al: Breakpoint analysis of Turner patients with partial Xp deletions: Implications for the lymphoedema gene location. J Med Genet 38:591, 2001
Bione S, Toniolo D: X chromosome genes and premature ovarian failure. Semin Reprod Med 18:51, 2000
Ford CE: Mosaics and chimaeras. Br Med Bull 25:104, 1969
Tharapel AT, Anderson KP, Simpson JL, et al: Deletion (X)(q26.1→q28) in a proband and her mother: Molecular characterization and phenotypic-karyotypic deductions Am J Hum Genet 52:463, 1993
Davison RM, Fox M, Conway GS: Mapping of the POF1 locus and identification of putative genes for premature ovarian failure. Mol Hum Reprod 6:314, 2000
Simpson JL: Genetics of female infertility. In Filicori M, Flamigni C (eds): Proceedings of the Conference, Treatment of Infertility: The New Frontiers. pp 37, 52 Boca Raton, FL, Communications Media for Education, 1998
Ogata T, Matsuo N: Turner syndrome and female sex chromosome aberrations: Deduction of the principal factors involved in the development of clinical features. Hum Genet 95:607, 1995
Wandstrat AE, Conroy JM, Zurcher VL, et al: Molecular and cytogenetic analysis of familial Xp deletions. Am J Med Genet 94:163, 2000
Thomas NS, Huson SM: Atypical phenotype in a female with a large Xp deletion. Am J Med Genet 104:81, 2001
Thomas NS, Sharp AJ, Browne CE, et al: Xp deletions associated with autism in three females. Hum Genet 104:43, 1999
Wilson MG, Modebe O, Towner JW, et al: Ullrich-Turner syndrome associated with interstitial deletion of Xp11.4 leads to p22.31 Am J Med Genet 14:567, 1983
Herva R, Kaluzewski B, de la Chapelle A: Inherited interstitial del(Xp) with minimal clinical consequences: With a note on the location of genes controlling phenotypic features. Am J Med Genet 3:43, 1979
Fraccaro M, Maraschio P, Pasquali F, et al: Women heterozygous for deficiency of the (p21 leads to pter) region of the X chromosome are fertile. Hum Genet 39:283, 1977
James RS, Dalton P, Gustashaw K, et al: Molecular characterization of isochromosomes of Xq. Ann Hum Genet 61:485, 1997
Massa G, Vanderschueren-Lodeweyckx M, Fryns JP: Deletion of the short arm of the X chromosome: a hereditary form of Turner syndrome. Eur J Pediatr 151:893, 1992
Knauff EA, Blauw HM, Pearson PL et al: Copy number variants on the X chromosome in women with primary ovarianinsufficiency. Fertil Steril. 2011 Apr95(5):1584-8.e1. Epub 2011 Feb 12.
Quilter CR, Karcanias AC, Bagga MR et al: Analysis of X chromosome genomic DNA sequence copy number variation associatedwith premature ovarian failure (POF). Hum Reprod. 2010 Aug25(8):2139-50. Epub 2010 Jun 22.
Dudding TE, Lawrence O, Winship I et al: Array comparative genomic hybridization for the detection of submicroscopic copynumber variations of the X chromosome in women with premature ovarian failure. Hum Reprod. 2010 Dec25(12):3159-60 author reply 3160-1. Epub 2010 Oct 16.
Aboura A, Dupas C, Tachdjian G et al: Array comparative genomic hybridization profiling analysis revealsdeoxyribonucleic acid copy number variations associated with premature ovarianfailure. J Clin Endocrinol Metab. 2009 Nov94(11):4540-6. Epub 2009 Oct 16.
Kok HS, van Asselt KM, van der Schouw YT et al: Genetic studies to identify genes underlying menopausal age. Hum Reprod Update. 2005 Sep-Oct11(5):483-93. Epub 2005 Jul 15.
Ochalski ME, Engle N, Wakim A et al: Complex X chromosome rearrangement delineated by array comparative genomehybridization in a woman with premature ovarian insufficiency. Fertil Steril. 2011 Jun95(7):2433.e9-15. Epub 2011 Apr 29.
Simpson JL, Elias S. Genetics in Obstetrics and Gynecology, 3rd edn. Philadelphia:WB Saunders, 2003
Simpson JL. Disorders of the gonads, genital tract, and genitalia. In: Principles and Practice of Medical Genetics, 5th edn. New York: Churchill-Livingstone, 2007:2005-92.
Jones MH, Furlong RA, Burkin H et al: The Drosophila developmental gene fat facets has a human homologue in Xp11.4 Hum Mol Genet. 1996 Nov5(11):1695-701.
Luoh SW, Bain PA, Polakiewicz RD et al: Zfx mutation results in small animal size and reduced germ cell number in maleand female mice. Development. 1997 Jun124(11):2275-84.
Dube JL, Wang P, Elvin J et al: The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol Endocrinol. 1998 Dec12(12):1809-17.
Di Pasquale E, Beck-Peccoz P, Persani L: Hypergonadotropic ovarian failure associated with an inherited mutation of human Am J Hum Genet. 2004 Jul75(1):106-11. Epub 2004 May 10.
Kovanci E, Heard MJ, McKenzie LJ et al. Mutation in the BMP15 gene is associated with premature ovarian failure. J Soc Gynecol Investig 2005 12:236A
Laissue P, Christin-Maitre S, Touraine P et al: Mutations and sequence variants in GDF9 and BMP15 in patients with prematureovarian failure. Eur J Endocrinol. 2006 May154(5):739-44.
Dixit H, Rao LK, Padmalatha VV et al: Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet. 2006 May119(4):408-15. Epub 2006 Mar 1.
Ellison JW, Wardak Z, Young MF et al: PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet. 1997 Aug6(8):1341-7.
Rao E, Weiss B, Fukami M et al: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failurein idiopathic short stature and Turner syndrome. Nat Genet. 1997 May16(1):54-63.
Belin V, Cusin V, Viot G et al: SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet. 1998 May19(1):67-9.
Shears DJ, Vassal HJ, Goodman FR et al: Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weilldyschondrosteosis. Nat Genet. 1998 May19(1):70-3.
Tachdjian G, Aboura A, Portnoi MF et al: Cryptic Xp duplication including the SHOX gene in a woman with 46,X,del(X)(q21.31) and premature ovarian failure. Hum Reprod. 2008 Jan23(1):222-6. Epub 2007 Nov 1.
Bione S, Sala C, Manzini C et al: A human homologue of the Drosophila melanogaster diaphanous gene is disrupted ina patient with premature ovarian failure: evidence for conserved function inoogenesis and implications for human sterility. Am J Hum Genet. 1998 Mar62(3):533-41.
Mumm S, Herrera L, Waeltz PW et al: X/autosomal translocations in the Xq critical region associated with prematureovarian failure fall within and outside genes. Genomics. 2001 Aug76(1-3):30-6.
Prueitt RL, Chen H, Barnes RI et al: Most Xautosome translocations associated with premature ovarian failure do not Cytogenet Genome Res. 200297(1-2):32-8.
Lacombe A, Lee H, Zahed L et al: Disruption of POF1B binding to nonmuscle actin filaments is associated withpremature ovarian failure. Am J Hum Genet. 2006 Jul79(1):113-9. Epub 2006 May 26.
Bione S, Rizzolio F, Sala C et al: Mutation analysis of two candidate genes for premature ovarian failure, DACH2 andPOF1B. Hum Reprod. 2004 Dec19(12):2759-66. Epub 2004 Sep 30.
Bione S, Toniolo D: X chromosome genes and premature ovarian failure. Semin Reprod Med. 200018(1):51-7.
Prueitt RL, Ross JL, Zinn AR: Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene. Cytogenet Cell Genet 89:44, 2000
Mansouri MR, Schuster J, Badhai J et al: Alterations in the expression, structure and function of progesterone receptor Hum Mol Genet. 2008 Dec 117(23):3776-83. Epub 2008 Sep 9.
Katsuya T, Horiuchi M, Minami S et al: Genomic organization and polymorphism of human angiotensin II type 2 receptor: noevidence for its gene mutation in two families of human premature ovarian failuresyndrome. Mol Cell Endocrinol. 1997 Mar 28127(2):221-8.
Wittenberger MD, Hagerman RJ, Sherman SL et al: The FMR1 premutation and reproduction. Fertil Steril. 2007 Mar87(3):456-65. Epub 2006 Oct 30.
Schwartz CE, Dean J, Howard-Peebles PN et al: Obstetrical and gynecological complications in fragile X carriers: a multicenterstudy. Am J Med Genet. 1994 Jul 1551(4):400-2.
Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D et al: Fragile X premutation is a significant risk factor for premature ovarian failure: Am J Med Genet. 1999 Apr 283(4):322-5.
Sullivan AK, Marcus M, Epstein MP et al: Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005 Feb20(2):402-12. Epub 2004 Dec 17.
Foresta C, Ferlin A, Gianaroli L et al: Guidelines for the appropriate use of genetic tests in infertile couples. Eur J Hum Genet. 2002 May10(5):303-12.