An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor (FSHR) gene and causes FSH resistance

Abstract

Follicle-stimulating hormone (FSH) mediated by its receptor (FSHR) is pivotal for normal gametogenesis. Inactivating FSHR mutations are known to cause hypergonadotropic hypogonadism with disturbed follicular maturation in females. So far, only very few recessive point mutations have been described. We report on a 17-year-old female with primary amenorrhea, hypergonadotropic hypogonadism and disturbed folliculogenesis. Chromosome analysis detected a seemingly balanced translocation 46,XX,t(2;8)(p16.3or21;p23.1)mat. FSHR sequence analysis revealed a novel non-synonymous point mutation in exon 10 (c.1760C4A, p.Pro587His), but no wild-type allele. The mutation was also found in the father, but not in the mother. Furthermore, molecular-cytogenetic analyses of the breakpoint region on chromosome 2 showed the translocation to be unbalanced, containing a deletion with one breakpoint within the FSHR gene. The deletion size was narrowed down by array analysis to approximately 163 kb, involving exons 9 and 10 of the FSHR gene. Functional studies of the mutation revealed the complete lack of signal transduction presumably caused by a changed conformational structure of transmembrane helix 6. To our knowledge, this is the first description of a compound heterozygosity of an inactivating FSHR point mutation unmasked by a partial deletion. This coincidence of two rare changes caused clinical signs consistent with FSH resistance.

Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome

“…It has been previously reported that complete loss of FSHR function yields a block in follicular growth from the primary stage onward in female patients (Allen et al, 2003;Kuechler et al, 2010;Meduri et al, 2003), whereas a partial loss of function mutation might lead to normal follicular development up to the small antral stage and a disruption at later stages (Beau et al, 1998;Touraine et al, 1999). However, a recent study has shown that early antral follicles were observed in a female patient who was found to carry a homozygous FSHR mutation (p.Arg59Term) with complete loss of function in vitro (Liu et al, 2017).…”

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

“…Ovaries showed a normal follicular development up to the small antral stage and a disruption at further stages. Primordial and intermediary follicles (few primary follicles) were observed Kuechler et al (2010) Minimum deletion in exons 9 and 10 and maximum deletion in exons 7-10 as FOXL2, NOBOX, LHX8, FOX10A, FOX03A, FIGLA, POU5F1, NANOS3, RASGRP3, KIT, (Qin et al 2012), which is not related to the FSHR gene located on chromosome 2. Existing paradigm in ovarian biology suggests that FSHR are expressed on the granulosa cells in ovaries and on the Sertoli cells in testes (Renner et al 2013, Siegel et al 2013.…”

Mutations and polymorphisms in FSH receptor: functional implications in human reproduction

“…Val were observed to lead to more adverse phenotypes such as primary amenorrhea (Achrekar et al 2010, Kuechler et al 2010). However, in vitro studies on the effect of the mutations in TMD on receptor trafficking have not yet been reported so far.…”