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Genetic investigation of four meiotic genes in women with premature ovarian failure

INRA, UMR 1198, ENVA, CNRS, FRE 2857, Biologie du Développement et Reproduction, Jouy-en-Josas F-78350, France¹ APHP, Department of Endocrinology and Reproductive Medicine, GH Pitié Salpêtrière, 47-83 Bd de l'Hôpital, 75651 Paris Cedex 13, France² Centre National de Génotypage,, 2 rue Gaston Crémieux, 91057 Evry, Cedex, France³ CNRS, UMR144, Génétique Moléculaire de la Recombinaison, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France and ⁴ INSERM, U709, Genomics and Epigenetics of Placentary Pathology, Hôpital Cochin, 123 Bld de Port Royal, 75014 Paris, France

(Correspondence should be addressed to B Mandon-Pépin; Email: beatrice.pepin{at}jouy.inra.fr)

Objective: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF).

Design: Case–control study.

Methods: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls).

Results: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V).

Conclusions: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.

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