Bone morphogenetic proteins (BMPs) exhibit broad spectrum of biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. BMPs are members of the transforming growth factor-β (TGF-β) family that bind to type II and type I serine-threonine kinase receptors, and transduce signals through Smad and non-Smad signalling pathways. BMPs together with other intraovarian growth factors are intimately involved in regulation of ovarian follicle recruitment, dominant follicle selection, ovulation, and atresia. We conducted a Whole Exome Sequencing on 69 Caucasian women with sporadic primary ovarian insufficiency (POI) and performed a bioinformatics analysis on a specific subset of 420 coherent candidate genes1. We found heterozygous variants in genes encoding BMP Receptors (BMPR1A and BMPR1B) in three POI women. POI is a major cause of infertility and is characterized by amenorrhea with an increase in gonadotropin levels and affects 1% of women before the age of 40. This disease may be the result of a variety of disorders caused by two main mechanisms: abnormal follicular development and follicle depletion due to a defect in their formation or an aberrantly rapid depletion of the stock. Although the majority of cases are idiopathic, POI can be triggered by autoimmune disease, infectious agents, iatrogenic effects, or genetic causes. It may also be part of syndromic diseases such as Turner, Fragile-X or Blepharophimosis Ptosis Epicanthus Inversus syndrome. The identified missense variants were located in the kinase domain of both receptors 1A and 1B and predicted to be deleterious in silico. We studied the signaling pathway of these receptors, Smad proteins phosphorylation, transcriptional activity and expression of Id1 and Smad7 target genes. We showed that these variants impaired the activity of the proteins. Consisting with these results, Bmpr1a −/− and Bmpr1b −/− mouse models develop infertility due to a reduced spontaneous ovulation and compromised cumulus expansion respectively. Altogether, our study describes the first BMPR1A and 1B mutations associated with isolated POI and increases the number of genes formally implicated as being responsible for this condition.
Reference: 1. Patiño LC et al. Hum Reprod. 2017; 32(7):15121520.
18 - 21 May 2019
European Society of Endocrinology