Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging.

Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction

Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an "African" variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient's geographical origin), that transthyretin-related amyloidosis can mimic

A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure

BACKGROUND Three variants of the human INHA gene have been reported to be associated with premature ovarian failure (POF) in case-control studies involving a small number of patients and controls. Since inhibin has a fundamental role in the control of ovarian function, it is important to establish the relevance of the reported variants for disease risk. METHODS Three independent POF cohorts, recruited in Northern and Central Italy and in Germany consisting of a total of 611 patients and 1084 matched controls, were genotyped for the three variants: -16C > T, -124A > G and 769G > A. RESULTS No significant difference was detected between allelic frequencies of the INHA promoter variants between POF patients and controls. The rare allele in the coding variant appeared to be more frequent among the control populations. CONCLUSIONS The association between the INHA promoter variants and POF could not be replicated, and our results suggest that this discrepancy is likely to be due to the small sample size of previous studies. The rare allele of the coding variant seems to exert a protective effect against loss of ovarian function, which should be confirmed in additional large and ethnically diverse cohorts