Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure.
OBJECTIVE
Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF).


METHODS
We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child.


RESULTS
We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions.


CONCLUSIONS
We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.
Laissue
Paul
P
INSERM 709, Genomics and Epigenetics of Placentary Pathology, Hôpital Cochin, Pavillon Baudelocque, 123 Bd de Port Royal, 75014, Paris, France.
Christin-Maitre
Sophie
S
Touraine
Philippe
P
Kuttenn
Frederique
F
Ritvos
Olli
O
Aittomaki
Kristiina
K
Bourcigaux
Nathalie
N
Jacquesson
Laetitia
L
Bouchard
Philippe
P
Frydman
Rene
R
Dewailly
Didier
D
Reyss
Anne-Céline
AC
Jeffery
Luke
L
Bachelot
Anne
A
Massin
Nathalie
N
Fellous
Marc
M
Veitia
Reiner A
RA
D000328:Adult; D000568:Amenorrhea / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D055430:Bone Morphogenetic Protein 15; D015331:Cohort Studies; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D055429:Growth Differentiation Factor 9; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA
C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins