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

Women with balanced translocations between the long arm of the X chromosome (Xq) and an autosome frequently suffer premature ovarian failure (POF). Tw o "critical regions" for POF which extend from Xq13 --> q22 and from Xq22 - -> q26 have been identified using cytogenetics. To gain insight into the me chanism(s) responsible for ovarian failure in women with X;autosome translo cations, we have molecularly characterized the translocation breakpoints of nine X chromosomes. We mapped the breakpoints using somatic cell hybrids r etaining the derivative autosome and densely spaced markers from the X-chro mosome physical map. One of the POF-associated breakpoints in a critical re gion (Xq25) mapped to a sequenced PAC clone. The translocation disrupts XPN PEP2, which encodes an Xaa-Pro aminopeptidase that hydrolyzes N-terminal Xa a-Pro bonds. XPNPEP2 mRNA was detected in fibroblasts that carry the transl ocation, suggesting that this gene at least partially escapes X inactivatio n. Although the physiologic substrates for the enzyme are not known, XPNPEP 2 is a candidate gene for POF. Our breakpoint mapping data will help to ide ntify additional candidate POF genes and to delineate the Xq POF critical r egion(s). Copyright(C)2000S.KargerAG,Basel.