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Genes and translocations involved in POF
David Schlessinger1, Luisa Herrera, Laura Crisponi
1Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland 21224, USA. schlessingerd@grc.nia.nih.gov
Abstract:
Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Foxl2 and interacting proteins, or with defined changes in the X chromosome.
Insights
Genetic factors influencing premature ovarian failure (POF) include autosomal and X-linked loci. The FOXL2 gene on chromosome 3 is implicated, while Xq translocations may affect ovarian development through chromosomal dynamics rather than specific gene disruption.
Area of Science:
- Genetics
- Reproductive Biology
- Genomics
Background:
- Gonadal dysgenesis, characterized by premature ovarian failure (POF) and ovarian follicle deficits, is linked to genetic alterations.
- A specific autosomal locus on chromosome 3 involves the FOXL2 gene, where mutations cause reduced follicle count via haploinsufficiency.
- X-linked loci, particularly a critical region on Xq, are also implicated in POF, though direct gene associations are currently weak.
Purpose of the Study:
- To explore the genetic underpinnings of premature ovarian failure (POF).
- To investigate the role of autosomal and X-linked genetic factors in ovarian development and follicle attrition.
- To propose models for POF etiology based on chromosomal abnormalities and gene interactions.
Main Methods:
- Analysis of autosomal and X-linked loci associated with gonadal dysgenesis.
- Identification of the FOXL2 gene on chromosome 3 and its role in ovarian follicle development.
- Examination of X; autosomal translocations, focusing on breakpoints in the critical region of Xq.
- Consideration of chromosomal pairing and X-inactivation dynamics in POF pathogenesis.
- Proposal for mouse models to study ovarian follicle development and attrition.
Main Results:
- Mutations in the FOXL2 gene on chromosome 3 lead to decreased ovarian follicles due to haploinsufficiency.
- X; autosomal translocations concentrate in a specific region on Xq, but their direct association with ovarian function genes is weak.
- POF associated with X translocations may result from altered chromosome pairing or X-inactivation, affecting folliculogenesis.
- The critical region on Xq exhibits unusual features, including proximity to the X-inactivation center and low recombination, suggesting sensitivity to structural changes.
Conclusions:
- Both autosomal (FOXL2) and X-linked factors contribute to premature ovarian failure.
- X-linked POF might arise from broader chromosomal abnormalities impacting meiotic checkpoints and apoptosis, rather than solely specific gene interruptions.
- Future research using mouse models with controlled gene expression and X chromosome alterations is crucial for elucidating POF etiology.