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


METHODS
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.
Mandon-Pépin
Béatrice
B
INRA, UMR 1198, ENVA, CNRS, FRE 2857, Biologie du Développement et Reproduction, Jouy-en-Josas F-78350, France. beatrice.pepin@jouy.inra.fr
Touraine
Philippe
P
Kuttenn
Frédérique
F
Derbois
Céline
C
Rouxel
Agnes
A
Matsuda
Fumihiko
F
Nicolas
Alain
A
Cotinot
Corinne
C
Fellous
Marc
M
D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics; D004706:Endodeoxyribonucleases; D004950:Esterases / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000473:pathology; D000099257:Meiotic Recombination Protein SPO11
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004706:Endodeoxyribonucleases; D004950:Esterases; D000099257:Meiotic Recombination Protein SPO11; C409221:MSH4 protein, human; C118481:MSH5 protein, human; C074556:DMC1 protein, human