Random X-chromosome inactivation

Ornithine transcarbamylase deficiency. This is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. If inactivation affects primarily the X chromosome bearing the mutant OTC gene, then a more favorable outcome can be anticipated. Conversely, the unfavorably lyonized female has a more active disease. 

Normal males inherit an X chromosome from their mother and a Y chromosome from then-father, whereas normal females inherit an X chromosome from each parent. Because the Y chromosome carries only about 30 protein-coding genes and the X chromosome carries hundreds of protein-coding genes, a mechanism must exist to equalize the amount of protein encoded by X chromosomes in males and females. This mechanism, termed X inactivation, ocairs very early in the development of female embryos. When an X chromosome is inactivated, its DNA is not transcribed into mRNA, and it is visuahzed under the microscope as a highly condensed Barr body in the nuclei of interphase cells. X inactivation has several important characteristics It is random—in some cells of the female embryo, the X chromosome inherited from the father is inactivated, and in others the X chromosome inherited from the mother is inactivated. Like coin tossing, this is a random process. 

X inactivation occurs early in the female embryo and is random, fixed, and incomplete. In a cell, all X chromosomes but one are inactivated. 

Normal females have two copies of the X chromosome, so they usually require two copies of the mutation to express the disease. However, because X inactivation is a random process, a heterozygous female will occasionally express an X-linked recessive mutation because, by random chance, most of the X chromosomes carrying the normal allele have been inactivated. Such females are termed manifesting heterozygotes. Because they usually have at least a small population of active X chromosomes carrying the normal allele, their disease expression is typically milder than that of a hemizygous male. 

Answer A. The most likely explanation for mild expression in a heterozygouscarrieris that when X inactivation occurred in the affected individual, the random process happened to inactivate most of the X chromosomes that carried the normal version of the factor VIII gene. Thus, most of the active X chromosomes in this individual would carry the mutation and would not produce factor VIII, leading to a clinically expressed deficiency. 

Greater variability of expression of the defect in females is due to random inactivation (lyoniza-tion) of one X chromosome during early embryonic development. Although all tissues from affected females contain cells that express the mutant gene, the relative distribution of normal and mutated cells among tissues is stochastic. Therefore, the clinical phenotype reflects primarily the combined effects of three independent factors ... 

Skewed X-inactivation (lyonization)—A process by which inactivation of the X chromosome is not random. 

The answer is a. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 97-158. Wilson, pp 23—39.) Females have two alleles for each locus on the X chromosome because of their 46,XX karyotype. One normal allele is by definition sufficient for normal function in X-linked recessive disorders, so that females with one abnormal allele are carriers instead of affected individuals. Only when the companion normal allele is disrupted or missing does the abnormal allele cause disease. The Lyon hypothesis predicts that X inactivation is early, irreversible, and random, but some females inactivate only the X chromosome carrying the normal allele. X autosome translocations may disrupt an X chromosome locus and cause disease because the translocated autosome must remain active to avert embryonic death nonrandom inactivation of the normal X chromosome thus ablates expression of its normal allele. Females with Turner s syndrome, like males with 46,XY karyotypes, have only one X chromosome and can be affected with X-linked recessive diseases. Conversely, females with triple X or trisomy X syndrome have three alleles at each X chromosome locus and are not affected with X-linked recessive disorders. Since choices c, d, and e each require two genetic changes, they are less common than choice a. 

Either the maternal or paternal X chromosome is inactivated at random... 

According to the Lyon hypothesis (L9), one X-chromosome in each cell is randomly inactivated in an early stage of embryonic development. As a result one half of the cells of a carrier of this enzyme deficiency should have normal amounts of the enzyme and the other should possess the amount that the individual with the defect has. Half of the cells of a mother of a Lesch-Nyhan patient should have no HPRT and half should have the normal amount the carriers of defects that result in 10% enzyme activity in the effected male offspring should have half of their cells normal and half with 10% of the enzyme. In addition, one would expect that the average value of the enzyme in a sample of red cells drawn from heterozygotes should have contained 50% normal activity in the case of the carrier of Lesch-Nyhan syndrome and the appropriate proportion in the carrier of a partial defect. 

X-linked recessive inheritance in females is impacted by a phenomenon known as X-inactivation or lyonization. A female s sex chromosomal constitntion is XX a male s sex chromosome constitntion is in XY. In females, a recessive disease mntation on one X chromosome should not resnlt in disease if the corresponding gene on the other X chromosome is normal. In actuality, the situation is more complicated. In females, one of the X chromosomes in each cell is randomly inactivated, a process known as X-inactivation. This is done to compensate for the donble state of X chromosomes in females relative to males. If the inactivation pattern is skewed so that the majority of X chromosomes with the normal gene are inactivated, the individual may be affected. The greater the skewed inactivation pattern, the more severe the disease. Becanse of this, the clinical phenotype of females with an X-linked recessive disorder, snch as ornithine transcarbamylase (OTC) deficiency, can range from nnaffected to severely affected. 

Another possible cause for deficiency of HGPRT activity in the female patient is the mutation of HGPRT gene on either maternal or paternal X chromosome and then nonrandom-selective, instead of random, inactivation of the X chromosome carrying the normal HGPRT gene, in a very early developmental stage. However, it should be very rare. 

It was postulated by Lyon that one or the other X chromosome in somatic cells of female mammals is at some early embryonic stage rendered inactive. The inactivated X chromosome, which may be of paternal or maternal origin, will remain inactive in all progeny of the embryonic cells. The major evidences cited by Lyon for this hypothesis were the occurrence of mottled or dappled coat colour phenotypes in heterozygous female mice and the existence of normal XO females. As a consequence of random inactivation of X chromosomes, females heterozygous for X linked traits exhibit mosaic phenotypes. Evidence in support of the hypothesis has been gathered in a variety of experiments. 

Allelic exclusion of allotypes is more complex than the exclusion of X linked traits in that several unlinked loci are involved. Nonetheless, a strong analogy may be drawn between the two phenomena. As in the exclusion of X alleles, allotype exclusion may be random and it is permanent in that peripheral blood lymphocytes and their progeny continue to produce the same allot)rpes . Whether the entire chromosome is involved is not known, nor is it known whether activation or inactivation is the basis of allelic selection of allotypes. 

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