RESUMO
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 approximately 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.
Assuntos
Insuficiência Ovariana Primária/genética , Translocação Genética , Cromossomo X/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , DNA/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Ligação Genética , Humanos , Hibridização in Situ Fluorescente , Camundongos , Modelos Genéticos , Dados de Sequência Molecular , Proteínas Nucleares/genética , Fatores de TranscriçãoRESUMO
Haploinsufficiency of FOXL2, a new forkhead transcription factor, causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), a rare developmental disorder affecting the eyelid and sometimes the ovary. A new study implicates FOXL2 as the first human gene required for the maintenance of ovarian follicles. The discovery of FOXL2 may provide insight into the causes of idiopathic premature ovarian failure, a disease that burdens many infertile couples.
Assuntos
Proteínas de Ligação a DNA/genética , Oftalmopatias/genética , Infertilidade Feminina/genética , Insuficiência Ovariana Primária/genética , Fatores de Transcrição/genética , Blefarofimose/genética , Blefaroptose/genética , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead , Humanos , SíndromeRESUMO
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).
