X chromosome rearrangements defined a critical region for premature ovarian failure (POF) that extended for >15 Mb in Xq. We have previously shown that the region could be divided into two functionally distinct portions and suggested that balanced translocations interrupting its proximal part, critical region 1 (CR1), could be responsible for POF through down regulation of ovary expressed autosomal genes translocated to the X chromosome. We report now that such position effect can indeed be demonstrated by analysis of breakpoint regions in somatic cells of POF patients and by the finding that the CR1 has a highly heterochromatic organization, very different from that of the euchromatic autosomal regions involved in the rearrangements. The chromatin organization of the POF CR1 is likely to be responsible of the epigenetic modifications observed in POF patients. The characteristics of the CR1 and its down regulation in oocytes very well explain its role in POF and the frequency of the POF phenotype in chromosomal rearrangements involving Xq. We also demonstrate a large and evolutionary conserved domain of the long arm of the X chromosome, largely corresponding to the CR1, that may have structural or functional roles, in oocyte maturation or in X chromosome inactivation.
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Web only appendices 46;9:585
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