To evaluate the implication of chromosome abnormalities in the etiology of premature ovarian failure (POF), 1000 patients with POF recruited at the Department of Cytogenetics of Farhat Hached Hospital (Sousse, Tunisia) between January 1996 and December 2008. Chromosome analyses were performed by using karyotyping and interphase fluorescent in situ hybridisation (FISH) using a centromeric probe of the chromosome X to look for low-level mosaicism of X-chromosome monosomy. Hundred and eight chromosomal abnormalities (10.8%) were found using karyotype analysis. Anomalies were detected in 61 cases out of 432 primary amenorrhea patients (14.12%) and 47 cases out of 568 secondary amenorrhea patients (8.27%). In 23 POF patients among 200 (11.5%) with 46,XX normal karyotype and explored using interphase FISH analysis, the percentage of cells with X-chromosome monosomy was significantly higher as compared with controls in the same age. The cytogenetic study of POF patients showed a high prevalence of chromosome anomalies either in primary or in secondary amenorrhoea. Mosaic X-chromosome s aneuploïdy was the most frequent abnormality and some patients with POF may be attributable to low-level 45,X/46,XX mosaicism detectable using FISH analysis.
Our data provide evidence in favour of the implication of FOXL2 variants in non-syndromic POF and confirm the regulatory interaction between FOXL2 and OSR2 whose perturbation might contribute to the palpebral abnormalities observed in BPES patients.
Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSA aetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors. Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556 women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.
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