FISH mapping of the sex-reversal region on human chromosome 9p in two XY females and in primates

Abstract

Accumulating evidence suggests that haploinsufficiency of a dosage-sensitive gene(s) in human chromosome 9p24.3 is responsible for the failure of testicular development and feminisation in XY patients with monosomy for 9p. We have used molecular cytogenetic methods to characterise the sex-reversing 9p deletions in two XY females. Fluorescence in situ hybridisation (FISH) with YACs from the critical 9p region containing an evolutionarily conserved sex-determining gene, DMRT1, is a very fast and reliable assay for patient screening. Comparative YAC mapping on great ape and Old and New World monkey chromosomes demonstrated that the critical region was moved from an interstitial position on the ancestral primate chromosome to a very subtelomeric position in chimpanzee and humans by a pericentric inversion(s). Pathological 9p rearrangements may be the consequence of an evolutionary chromosome breakpoint in close proximity to the sex-reversal region.

Case Report Familial balanced translocation leading to an offspring with phenotypic manifestations of 9p syndrome

“…Alterations involving the candidate sex-determining gene DMRT1 are often associated with sex reversal and gonadal dysgenesis (Smith et al, 1999;Shan et al, 2000). Defective testicular development and XY feminization occur when this gene is present in hemizygosis (Shan et al, 2000). Moreover, a great variability in impaired development in male cases of monosomy 9p has been reported, confirming the cryptorchidism and micropenis observed in Patient 1 and Patient 2, respectively.…”

“…Deletion of the KANK1 gene causes parent-of-origin-dependent inheritance of familial cerebral palsy that occurs only in individuals inheriting the deletion from the father (Lerer et al, 2005). Alterations involving the candidate sex-determining gene DMRT1 are often associated with sex reversal and gonadal dysgenesis (Smith et al, 1999;Shan et al, 2000). Defective testicular development and XY feminization occur when this gene is present in hemizygosis (Shan et al, 2000).…”

Molecular cloning of doublesex and mab-3-related transcription factor 1, forkhead transcription factor gene 2, and two types of cytochrome P450 aromatase in Southern catfish and their possible roles in sex differentiation

“…Deletion of a chromosome segment containing DMRT1 resulted in sex reversal in humans (Raymond et al 1999a). Furthermore, DMRT1 was found to be expressed in the genital ridge before sex differentiation, specifically in the testis but not in the ovary (De Grandi et al 2000, Shan et al 2000b. Mouse Dmrt1 was also found to be expressed in the genital ridge during the sensitive period of sex determination and its expression was found to persist during the whole process of gonad differentiation.…”

“…However, unlike Dmrt1a, which is exclusively expressed in the gonads, Dmrt1b is extensively expressed in other nongonadal tissues including the intestine and kidney of the male fish, indicating that this isoform may have other functions. Some previous reports also demonstrated the expression of Dmrt1 outside the gonad such as in the chicken Mullerian tract (Shan et al 2000b, Smith et al 2003. The Mullerian tract still belongs to the reproductive system, but the intestine and kidney are not part of the reproductive system.…”

Sex-specific expression of an evolutionarily conserved male regulatory gene, <i>DMRT1</i>, in birds

“…By comparative gene mapping we have recently identified a large segment of conserved chromosomal synteny between the chicken Z and human chromosome 9 (Nanda et al, 1999;. Interestingly, monosomy for the distal short arm of human chromosome 9 interferes with normal testicular development and leads to XY feminization (Flejter et al, 1998;Raymond et al, 1999a;Shan et al, 2000). The critical region for sex reversal has been narrowed down to band 9p24.3 and contains two candidate genes, DMRT1 (Doublesex and Mab-3 related transcription factor 1) and DMRT2, which are expressed in the adult testis.…”