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Sex chromosome-linked disease

Sex-Linked Inheritance and Disease

The so-called sex-linked diseases are caused by faulty genes located on the sex chromosomes. Characteristic inheritance patterns can be observed depending on which chromosome they are associated with, and whether they are dominant or recessive. These were first discovered as a result of pioneering work by Thomas Hunt Morgan in the early 1900s on fruit flies. He found an abnormal inheritance of white eye phenotype within the red eye wild type background, and went on to confirm the theory of chromosomes. There are 3 patterns by which sex-linked conditions or characteristics can be passed through a family, each with a variety of associated diseases.

X-Linked Recessive

Females carrying a single disease allele are carriers and unaffected as the wild type copy of the allele compensates for the mutated allele. If they pass this disease carrying X-chromosome on to a daughter they too will be carriers, however if they pass it on to a son the child will be affected. Males can not be carriers and are always affected due to hemizygosity; with only one X-chromosome, there is not a second wild type allele to compensate for the mutation.

Fathers will not pass this on to sons as the Y-chromosome must be transmitted, though they can pass it on to their daughters. Daughters of diseased males will usually be carriers, but can be affected in the unlikely case of them inheriting another disease causing allele from their mother.  This mode of inheritance was the pattern that Morgan elucidated with his X-linked recessive white eye allele. An example of a family pedigree for a condition is demonstrated in Figure 1.

Figure 1 - X-Linked Recessive Pedigree

There are a variety of diseases that are inherited in this fashion. One of the most common of these diseases is X-linked recessive haemophilia. Affected individuals have genetic mutations in clotting factors (most commonly clotting factor VIII) and therefore have impaired ability to stop bleeding after a blood vessel is broken. 1 in 10,000 have the disease, most of which are males as it is linked to the X-chromosome.

X-Linked Dominant

Both Males and Females carrying a single copy of the allele are affected. Females will pass on to half of their children in a sex-unspecific manner. Males will pass on to all their daughters and none of their sons. This inheritance pattern is shown in Figure 2, an example pedigree.

Figure 2 - X-Linked Dominant Pedigree

An X-linked dominant form of the disease hypophosphatemia (a form of rickets) exists. This disease occurs due to an excess excretion of phosphates from the body. This results bones being unable to properly mineralise, giving short stature and bow-leggedness in affected individuals. The underlying genetic cause is mutations to the X-chromosome gene, PHEX. Encoded at this locus is a peptidase key for the down-regulation of hormones involved in inducing phosphate excretion (phosphatonins). In X-linked hypophosphatemia a mutant PHEX is inherited, resulting in the protein product being inefficient, inactive or completely absent, and therefore the inability to degrade the pro-excretory hormones. This condition affects 1 in 20,000 people, manifesting in childhood.

One unusual example of an X-linked dominant disease attracted infamy in the 19th Century as affected people travelled around the world making money off of their disease. These were the circus performers known as ape-faced women or bearded ladies. Julia Pastrana, a particularly famous example, was covered from head to toe in hair even including some outgrowth inside her mouth. Her underlying condition was X-linked Dominant congenital generalised hypertrichosis. This is very rare and has only been documented in about 50 individuals, though other forms of hypertrichosis are more prevalent. The condition is believed to result from the misregulation of the X-chromosome gene SOX3 through an insertion into an adjacent palindromic sequence

Examples of X-linked dominant disease are rare, but other similar forms of inheritance exist, as in the case of Fragile-X syndrome, the most common form of inheritable mental retardation. The mutant FMR1 gene, which resides on the X-chromosome, arises due to an expansion of a CGG triplet repeat sequence in the 5' untranslated region of the gene. This recurring region exits in a pre-mutational state that has little phenotypic affect, however, once over 200 copies have accumulated the individual displays symptoms. With further expansion the severity of the condition increases. Copy number rises due the replication machinery slipping when it tries to read the repetitive region. As this mutant locus increases in size it promotes its own hypermethylation and transcription from of this gene consequentially stalls. The protein produced from this locus, FMRP, is known to be functionally important in the localisation of mRNAs in neurones, only allowing their translation once they are in the correct position. Without this transport regulation synaptic plasticity is lost and males with the full mutation have IQs of roughly 40.

Y-Linked

These conditions affect only males and carrying a copy of the mutated allele always results in the disease phenotype because men only have one copy of Y. It is inherited from father to son affecting all males in a lineage. This is represented in the pedigree in Figure 3.

Figure 3 - Y-Linked Pedigree

Y-linked diseases are generally rare as there are very few genes contained on this relatively small chromosome. It has been linked to male infertility as a number of genes crucial to spermatogenesis are present here. One such condition, Sertoli-only cell syndrome, results in the complete absence of the germ cells in the testis. This is due to deletions within the AZFa genomic region which is home to a number of testis specific genes.

Further reading

Kingston, H. M., 2002. ABC of Clinical Genetics, London, BMJ Books. (A succint textbook with a section on all types of sex linked inheritance, including sample pedigrees)

Miko, I., 2008.Thomas Hunt Morgan and sex linkage.Nature Education, 1, 1. (A description of Morgans pioneering work into sex-linked inheritance.)

Dreznerd, M. K. 2000. PHEX gene and hypophosphatemia. Kidney International, 57, 9-18. (Summary of hypophosphatemia and the role of PHEX.)

Garber, K.B., Visootsak, J. & Warren, S.T., 2008. Fragile X syndrome. European Journal of Human Genetics 16, 666-672. (Good review of the various aspexts of Fragile-X Syndrome.)

Zhu, H. et al., 2011. X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3. American Journal of Human Genetics 88, 819-826. (Recent results which map the cause of X-Linked Congenital Hypertrichosis. This includes a real-life example of a pedigree tree for a X-linked recessive condition.)

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