Variants of the BMP15 gene in a cohort of patients with premature ovarian failure

BACKGROUND Bone morphogenetic protein 15 (BMP15) is an oocyte-derived growth factor acting as a major player in follicle differentiation in mammals. Mutations in the BMP15 gene, some of which lead to defective secretion of bioactive dimers, have been associated with premature ovarian failure (POF) i...

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Published in:Human reproduction (Oxford) 2010-06, Vol.25 (6), p.1581-1587
Main Authors: Tiotiu, D., Alvaro Mercadal, B., Imbert, R., Verbist, J., Demeestere, I., De Leener, A., Englert, Y., Vassart, G., Costagliola, S., Delbaere, A.
Format: Article
Language:English
Subjects:
Adult
Alleles
Amenorrhea - genetics
BMP15
Bone Morphogenetic Protein 15 - genetics
Female
Genetic Predisposition to Disease
Humans
Mutation
Polymerase Chain Reaction
polymorphism
Polymorphism, Single Nucleotide
premature ovarian failure
Primary Ovarian Insufficiency - genetics
Promoter Regions, Genetic
Surveys and Questionnaires
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Summary:BACKGROUND Bone morphogenetic protein 15 (BMP15) is an oocyte-derived growth factor acting as a major player in follicle differentiation in mammals. Mutations in the BMP15 gene, some of which lead to defective secretion of bioactive dimers, have been associated with premature ovarian failure (POF) in humans. METHODS Fifty patients diagnosed with POF with a normal karyotype were included in the study. After DNA extraction and amplification by PCR, the entire coding sequence and intron–exon junctions of BMP15 gene were analysed in the cohort of POF patients and in a control group of 214 patients. RESULTS Nine variants of the BMP15 gene including six missense substitutions and one insertion of three nucleotides were identified in the POF group. Three of them were previously described as single nucleotide polymorphisms and were also found in the control group. Two variants (H81R and G199R) have not been previously described and were not identified among controls but were not predicted to be deleterious. One variant (A180T) was identified among two POF cases, and also in two controls. One variant (F194S), predicted as potentially deleterious, was identified for the first time in a POF patient but also identified in one control. One variant (L148P), potentially deleterious, previously reported in POF patients, was identified for the first time among controls. The variant 788insTCT, previously identified among POF patients, probably has a low biological impact as it was also found in control patients and is a common polymorphism in sub-Saharan African populations. CONCLUSIONS Various missense variants of the BMP15 gene were identified among patients with POF. For most variants, the impact of the amino-acid substitution on the protein structure and function was predicted to be low. The two variants predicted as potentially deleterious were also identified among controls and could be considered as rare polymorphisms. Although some of these variants could contribute to the development of POF in a complex manner, the demonstration of their role in the pathogenesis of POF requires additional functional studies.
ISSN:0268-1161
1460-2350
DOI:10.1093/humrep/deq073