Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene Ross JL, et al .
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).
Ovarian function
Follicle development
Comment
Identifying a Novel Role for X-prolyl Aminopeptidase (Xpnpep)2 in CrVI-Induced Adverse Effects on Germ Cell Nest Breakdown and Follicle Development. Banu SK et al. (2015) Environmental exposure to endocrine disruptors (EDCs) is one of the causes for premature ovarian failure (POF). Hexavalent chromium (CrVI) is a heavy metal EDC, widely used in more than 50 industries including chrome plating, welding, wood processing and tanneries. Recent data from USEPA indicate increased levels of Cr in drinking water from several cities in the U.S., which potentially predisposes Americans to various health problems. Our recent finding demonstrated that gestational exposure to CrVI caused POF in F1 offspring. The current study was performed to identify the molecular mechanism behind CrVI-induced POF. Pregnant rats were treated with 25 ppm potassium dichromate (CrVI) from Gestational Day (GD) 9.5-14.5 through drinking water, and the fetuses were exposed to CrVI through transplacental transfer. Ovaries were removed from the fetuses or pups on Embryonic Day (E) 15.5, 17.5 or Postnatal Day (PND)-1, -4 and 25, and various analyses were performed. Results showed that gestational exposure to CrVI: (i) increased germ cell/oocyte apoptosis and advanced germ cell nest (GCN) breakdown; (ii) increased X-prolyl aminopeptidase (Xpnpep)2, a POF marker in human, during GCN breakdown; (iii) decreased Xpnpep2 during postnatal follicle development; (iv) Xpnpep2 inversely regulate the expression of Col1, Col3 and Col4 in all the developmental stages studied; (v) increased co-localization of Xpnpep2 with Col3 and Col4. Thus CrVI advanced GCN breakdown and increased follicle atresia in F1 female progeny by targeting Xpnpep2.//////////////////
Expression regulated by
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Ovarian localization
Comment
Follicle stages
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene. Prueitt RL et al. 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).