Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes

Abstract

Balanced translocations with breakpoints in a critical region of the X chromosome, Xq13→q26, are associated with premature ovarian failure (POF). Translocations may cause POF either by affecting expression of specific X-linked genes essential for maintenance of normal ovarian function or by a chromosomal effect such as inhibition of meiotic pairing or altered X inactivation. We previously mapped seven Xq translocation breakpoints associated with POF to ∼75-kb intervals. One translocation disrupted an aminopeptidase gene, XPNPEP2. We have now refined the map location of the remaining six breakpoints with respect to known genes and transcription units predicted from the draft human genome sequence. Only one of the six breakpoints disrupts a gene, DACH2, the human ortholog of a mouse gene expressed in embryonic nervous tissue, sensory organs, and limbs. DACH2 has no obvious relationship to ovarian function. The other five breakpoints fall in apparently intragenic regions. Our results are most consistent with models for POF associated with X;autosome translocations that involve generalized chromosome effects.

Genes involved in human premature ovarian failure

“…Only the DIAPH2 gene, a human homolog of the Drosophila melanogaster diaphanous gene affecting spermatogenesis and oogenesis, was found disrupted by a breakpoint in a family with POI, but no mutation demonstrated its role in ovarian function nor that of the others candidates. However, most breakpoints described in POI patients were frequently mapped in Xq21, outside of genic regions, consistent with models for POI associated with X to autosome translocations that involve extra X chromosome effects (Mumm et al 2001, Prueitt et al 2002. These observations suggest the hypothesis that chromosomal rearrangements due to an epigenetic effect of the active X chromosome may account for a position effect on promoters of autosomal genes when involved in balanced translocations (Rizzolio et al 2007).…”

An excess of chromosome 1 breakpoints in male infertility

“…32 Molecular mapping of several of these breakpoints have shown that they are scattered over the entire critical region, supporting the idea that integrity of a specific chromosomal domain may be important for the development of female germ cells. 33 Since the chromosome 1 breakpoints in male infertility do not seem to be associated with any specific chromosomal region(s), either at the cytogenetic or at the molecular level, we suggest that chromosome 1 harbours a large chromosomal domain, the integrity of which is important for normal spermatogenesis.…”

Disruption ofHDXgene in premature ovarian failure

“…[Cremers et al 1990], and DIAPH2 (MIM * 300108) in Xq22 [Bione et al 1998]. However, most of the breakpoints mapped in the Xq region described in POF patients are intergenic [Mumm et al 2001;Prueitt et al 2002]. Only the DIAPH2 gene was disrupted by translocation in a family with POF affecting oogenesis [Bione et al 1998].…”