Hypergonadotropic Ovarian Failure Associated with an Inherited Mutation of Human Bone Morphogenetic Protein-15 (BMP15) Gene

Abstract

Hypergonadotropic ovarian failure is a common cause of female infertility. It is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis (OD). Most OD cases are associated with major X-chromosome abnormalities, but the pathogenesis of this disorder is still largely undefined in patients with a normal karyotype. Animal models showed the important role in female reproduction played by the product of a gene located at Xp11.2 in humans (BMP15). BMP15 is an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. We report two sisters with a normal karyotype who are affected with hypergonadotropic ovarian failure due to OD. The familial presentation suggested a genetic origin, and candidate genes were screened for mutations. A heterozygous nonconservative substitution in the pro region of BMP15 (Y235C) was identified in both sisters but not in 210 control alleles. This mutation was inherited from the father. Mutant BMP15 appears to be processed abnormally, is associated with reduced GC growth, and antagonizes the stimulatory activity of wild-type protein on GC proliferation. In conclusion, the first natural mutation in human BMP15 is associated with familial OD, indicating that the action of BMP15 is required for the progression of human folliculogenesis. This condition represents an exceptional example of X-linked human disease exclusively affecting heterozygous females who inherited the genetic alteration from the unaffected father. BMP15 defects are involved in the pathogenesis of hypergonadotropic ovarian failure in humans.

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure

“…Among these, GDF9 and BMP15 and more recently meiosis genes have become candidate genes for POF (13)(14)(15)27). However, they demonstrate variable clinical expressions, and their clinical relevance is not clear.…”

“…In non-syndromic forms, rare mutations in the FSH have been described, (1,(7)(8)(9), and our group has previously identified homozygous or compound heterozygous mutations of the FSHR gene in three POF patients (10)(11)(12). Some variants of other genes, such as BMP15, GDF9, and NOBOX and more recently some mutations of NR5A1 have also been reported (13)(14)(15)(16)(17)(18). Nevertheless, mutations affecting all of these genes account for a small minority of all cases of ovarian dysfunction, which suggest that there are additional factors that remain to be identified.…”

Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure

“…Recently, a point mutation in BMP15 has been associated with POF (16). A 4 bp deletion of GDF9 apparently leading to a premature stop codon has been reported in two sisters with twins from one family (17).…”

Understanding Ovarian Life Cycle

“…Örne¤in, oosit kaynakl› BMP-6 and BMP-15 (GDF-9B) genleri olmayan farede normal folikül geliflimi ve fertilite izlenirken (41,42) BMP-15 mutasyonu insan ve koyunda prematür over yetmezli¤i ile karakterizedir (43,44) .…”