TRINUCLEOTIDE REPEATS AND SEX DETERMINATION

by M. Italiano

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Recent advances in molecular biology have led to the identification of the SRY testis detemining gene (Sinclair, et. al., 1990; Koopman, et. al., 1991). Testicular tissue may occur in individuals lacking SRY (some XX males and most true hermaphrodites) (Pereira, 1991), and there are individuals who lack testicular tissue despite the presence of an intact SRY (some XY females with gonadal dysgenesis) (Pivnick, 1992). These cases suggest other genes, X-linked and autosomal, which are actively involved in the primary (gonadal) sex determining pathway.

Other data may require alternative molecular insights. For instance, it has been observed that XX males and XX true hermaphrodites often occur within the same family history (Skordis, et. al., 1987). In some cases, the mode of inheritance is known to be autosomal in nature. Since Lyonization can't explain this finding, it remains to be determined how a common genetic defect causes one member of a family to become a male with testes, and the other, a true hermaphrodite with testicular and ovarian tissue. (See discussion in Wachtel, 1994).

This can easily be explained, however, if we consider trinuceotide expansion. Upstream to the translation site of certain genes there is an expanded region of trinucleotide repeats, which is unstable; it can expand to greater lenghts when transmitted to successive generations (Richards and Sutherland, 1992). Each subsequent generation can receive a chain of these repeats which is elongated more than that of its predecessor. When the number of repeats exceeds a particular limit, they interfere with the translation of the gene in question. (Yu, et. al., 1992). This can result in consequences such as disease, the severity of which is correlated with the number of repeats involved in the expansion. (Harley, H.G., et. al., 1993).

It is suggested here, that trinucleotide repeats would cause sex reversal, the severity of which would also be correlated with the number of repeats in the expansion. Severity in this context apllies to the variability of partial sex reversal (XX true hermaphroditism) as opposed to complete sex reversal (XX male syndrome).

This would explain the autosomally-linked familial pattern of sex reversal observed by Skordis, et. al. (1987), as well as that in American cocker spaniels described by Selden, et. al. (1978). In the latter study a true hermaphrodite whelped an XX male with unambiguous testes. Assuming that the pup's testes were inherited from its mother, this could be explained by trinucleotide repeat expansion, in conjuntion with differential methylation patterns, which are usually derived from the female gamete (Harley, et. al., 1993; McConkie-Rosell, et. al., 1993; Yu, et. al., 1992).





REFERENCES


Harley, H.G., et. al. (1993) Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in Myotonic Dystrophy. Am. J. Hum. Genet., 53, 1164-1174.

Koopman, P. et. al. (1991) Male development of chromosomally femal mice transgenic for SRY. Nature, 351, 117-121.

McConkie-Rosell, A., et. al. (1993) Evidence that methylation of the FMR-1 locus is resonsible for sex variable phenotypic expression of the fragile X syndrome. Am J. Hum. Genet., 53, 800-809.

Pereira, E.T. (1991) Use of probes for ZFY, SRY, and the Y pseudoautosomal boundary in XX males, XX true hermaphrodites, and an XY female. J. Med. Genet., 28, 591-595.

Pivnick, E.K. (1992) Mutations in the conserved domain of SRY are uncommon in XY gonadal dysgenesis. Hum. Genet., 90, 308-310.

Richards, R.I. and Sutherland, G.R. (1992) Heritable unsatble DNA sequences. Nature Genet., 1, 7-9.

Seldon, J.R., et. al. (1978) Genetic basis of XX male syndrome and XX true hermaphrodites: Evidence in the dog. Science, 201, 644-646.

Sinclair, A.H., et. al. (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature, 346, 240-244.

Skordis, N., et. al. (1987) Familial XX males coexisting with familial 46 XX true hermaphrodites in same pedigree. J. Pediatr., 110, 244-248.

Wachtel, S.S. (1994) XX Sex Reversal in the Human. Chapter 12 in Wachtel, S.S. (edit.) Molecular Genetics of Sex Determination. Academic Press.

Yu, S., et. al. (1992) Fragile-X syndrome: unique genetics of the heritable unstable element. Amer. J. Hum. Genet., 50, 968-980.