NOBOX is a strong autosomal candidate gene in Tunisian patients with primary ovarian insufficiency.

Premature ovarian insufficiency (POI) affects approximately 1% of women before the age of 40. Genetic contribution is a significant component of POI. In this context, heterozygous mutations in NOBOX, BMP15 and GDF9 have been reported. The objective of our study was to evaluate the prevalence of these genes mutations in 125 unrelated Tunisian patients diagnosed with POI. The screening of NOBOX gene revealed three missense mutations (p.Arg117Trp; p.Gly91Trp and p.Pro619Leu) in eight patients. These mutations were not found in a 200 ethnically matched women without fertility problem. The sequencing of BMP15 and GDF9 gene revealed only previously reported variants. In contrast to previous studies, the prevalence of BMP15 variations is not higher than in the control population. Conversely, 6.4% of the cases present a NOBOX mutations; this high prevalence strengthens the consideration of NOBOX gene as strong autosomal candidate for POI.

[Place of pelvic ultrasonography using transabdominal technique in the investigation of premature ovarian failure]. / Place de l'échographie pelvienne réalisée par voie sus-pubienne dans l'exploration de l'insuffisance ovarienne prématurée.

OBJECTIVES: The aim of the present study was to characterize women with premature ovarian failure (POF) by their ovarian ultrasonographic appearances using transabdominal technique to establish the relationship to clinical, hormonal status, and genetic analysis. PATIENTS AND METHODS: We studied a cohort of 80 patients suffering from POF. The surface of the ovary was calculated and we identified the detection or not of follicles. RESULTS: The detection of the two ovaries by ultrasound was positive in 33 patients; only one ovary was identified in seven patients; none was noted in 40 patients. The surface of the ovaries ranged between 0.74 et 5.92 cm(2) (2.2+/-1.13 cm(2)). Ultrasonography identified follicles in 23 patients (28.75%). The presence of follicles suggested at ultrasonography was detected in 14 cases (70%) in normal-sized ovaries (> or =2 cm(2)) and in nine cases (45%) in small-sized ovaries (p=0.1). No significative statistical difference was found between the ultrasonographic appearances and the type of amenorrhea, pubertal development, hormonal status (estradiol, testosterone and delta-4-androstendione) and the chromosomal analysis. CONCLUSION: The clinical and hormonal status and the genetic analysis can't predict the presence or not of follicles in the ovaries of patients with POF.

Cytogenetic analyses of premature ovarian failure using karyotyping and interphase fluorescence in situ hybridization (FISH) in a group of 1000 patients.

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.

Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2.

BACKGROUND: FOXL2 encodes a forkhead transcription factor whose mutations are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), involving craniofacial/palpebral abnormalities often associated with premature ovarian failure (POF). RESULTS: We describe a FOXL2 variant (p.Gly187Asp) in a case of POF without BPES. The subcellular localisation of FOXL2-G187D was normal but its transactivation capacity tested on two reporter promoters, one of which should be relevant to the ovary, was significantly lower than that of normal FOXL2. However, FOXL2-G187D was able to activate strongly a reporter construct driven by the promoter of Osr2 (odd-skipped related 2 transcription factor), which we have suggested to be a crucial target of FOXL2 in the craniofacial region. This is compatible with the absence of BPES in our patient. CONCLUSIONS: 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.

[Genetic analysis of premature ovarian failure: role of forkhead and TGF-beta genes]. / Analyse génétique des insuffisances ovariennes prématurées: implication des gènes forkhead et TGF-beta.

Premature ovarian failure is a common pathology affecting 1% of women. Although multiple etiologies have been described the majority of cases are idiopathic. Forkhead transcription factors as FOXL2 and FOXO3A are of particular interest in the research of genetic factors related with the pathology as they are present in diverse developmental pathways and ovarian physiology. Similarly, some TGF-beta factors (i.e. BMP 15 and GDF-9) have been demonstrated to play a key role in the regulation, at ovarian level, of female reproduction. In recent years numerous studies have been performed in order to elucidate the implication of these factors in the ovarian physiopathology. The aim of this manuscript is to describe some of these advances in the context of premature ovarian failure.