Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene

Abstract

Women with balanced translocations between the long arm of the X chromosome (Xq) and an autosome frequently suffer premature ovarian failure (POF). Two “critical regions” for POF which extend from Xq13→q22 and from Xq22→q26 have been identified using cytogenetics. To gain insight into the mechanism(s) responsible for ovarian failure in women with X;autosome translocations, we have molecularly characterized the translocation breakpoints of nine X chromosomes. We mapped the breakpoints using somatic cell hybrids retaining the derivative autosome and densely spaced markers from the X-chromosome physical map. One of the POF-associated breakpoints in a critical region (Xq25) mapped to a sequenced PAC clone. The translocation disrupts XPNPEP2, which encodes an Xaa-Pro aminopeptidase that hydrolyzes N-terminal Xaa-Pro bonds. XPNPEP2 mRNA was detected in fibroblasts that carry the translocation, suggesting that this gene at least partially escapes X inactivation. Although the physiologic substrates for the enzyme are not known, XPNPEP2 is a candidate gene for POF. Our breakpoint mapping data will help to identify additional candidate POF genes and to delineate the Xq POF critical region(s).

Turner's Syndrome

“…Loss of interstitial or terminal long-arm material of the X chromosome (Xq) can result in short stature and primary or secondary ovarian failure. 15 Deletions distal to Xq21 appear to have no effect on stature. In general, loss of the short arm (Xp) results in the full phenotype.…”

Insight into the Genomics of Premature Ovarian Failure

“…Identification of deletions and translocations in POF1 and POF2 regions has suggested several POF-candidate genes, such as [36][37][38], although very few mutations have actually been detected in these loci [39,40].…”

Genes involved in human premature ovarian failure

“…The 'position effect' is a mechanism involving the deletion or translocation of regulatory domains to different position on the genome that might cause changes in gene transcription. Transcriptional characterization of breakpoint regions in O40 balanced translocations led to the identification of five genes interrupted by translocations: the XPNPEP2 (MIM *300145) gene in Xq25 (Prueitt et al 2000), the POF1B (MIM *300603) gene in Xq21.2, the DACH2 (MIM *300608) gene in Xq21.3 (Bione et al 2004), the CHM (MIM *300390) gene in Xq21. 2 (van Bokhoven et al 1994), and the DIAPH2 (MIM *300108) gene in Xq22 (Bione et al 1998).…”