ObjectiveThe goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4),MSH5, andS. cerevisiaehomolog (SPO11), were associated with premature ovarian failure (POF).DesignCase–control study.MethodsBlood 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).ResultsA single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 ofMSH5, 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 ofDMC1gene that led to an alteration of the amino acid composition of the protein (M200V).ConclusionsThe symptoms of infertility observed in theDMC1homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of theMSH5gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function.MSH5andDMC1mutations may be one explanation for POF, albeit uncommon.