FSHβ Gene Mutations in a Female with Partial Breast Development and a Male Sibling with Normal Puberty and Azoospermia

Abstract

FSH is a dimeric pituitary glycoprotein hormone that regulates gonadal function. Human mutations in the FSH beta gene have been shown to produce complete deficiency states in which pubertal development and reproductive capacity are inhibited. To date, no patients with partial or complete pubertal development due to FSH beta mutations have been documented in humans. We describe and characterize affected siblings, a male and a female, with evidence of pubertal development due to homozygosity for a Tyr76X nonsense mutation in the FSH beta gene. In vitro analysis of this mutant demonstrates unmeasurable FSH by immunoassay and by two different bioassays, using either cAMP (homologous FSH bioassay) or estradiol (rat granulosa cell assay) as the endpoints. In additional in vitro analyses, mutants previously found in patients with a phenotype of complete FSH deficiency (Cys51Gly and Val61X) and the Tyr76X were compared in the same immuno- and bioassays. All mutations failed to produce measurable FSH by all assays. Unexpectedly, these siblings with isolated FSH deficiency due to a nonsense FSH beta mutation had some evidence of puberty, suggesting that other factors might preserve gonadal steroidogenesis in the absence of FSH or that current bioassays cannot discriminate among very low FSH levels.

Association of novel SNPs in gonadotropin genes with sperm quality traits of Boer goats and Boer crosses

“…It could be that the homozygote genotype with low frequency might have been eliminated because of its extremely poor semen quality or sterility (Dai et al 2009). Previous literature reported some mutations in the FSHβ gene that could cause azoospermia in homozygous men (Lindstedt et al 1998;Layman et al 2002;Simoni et al 2016), although there is no report of association between SNPs of FSHΒ gene and sterility in Boer or Boer-crosses bucks. The low frequency of the favourable allele of FSHΒ3-c was probably due to the lack of selection for improving semen quality in the population.…”

“…Ohta et al (2007) elucidated that FSH is required for the initiation and maintenance of the quality and quantity in spermatogenesis. In addition, association between some of the single mutation of FSH with male fertility disorder in human (Layman et al 2002) shows the role of normal FSH on fertility and semen quality. Layman (2000) also reported that FSHβ knockout mice showed a deficiency of sperm cells in their semen.…”

“…Interaction among gonadotropin-releasing hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone are essential for spermatogenesis (Barth et al 2008). There are some single-nucleotide polymorphisms (SNPs) in FSH and LH genes, which cause a lack of or deficiency in FSH or LH hormones that consequently cause defects in reproduction and fertility of men (Layman et al 2002;Lee et al 2003;Mafra et al 2010).…”

Endocrine Tests and/or Testicular Volume Are Not Predictive of Successful Sperm Retrieval by Multiple Testicular Sperm Extraction in Non-Obstructive Azoospermia

“…Azoospermia has been a consistent nding in men with loss of function mutations in FSHβ. [28,29] Serum FSH could predict the existence of sperm which could be retrieved by conventional TESE. [27] Elevated plasma levels of FSH above 19.4 mIU/mL can suggest no spermatogenesis and hence an unsuccessful sperm retrieval.…”

Structure-function relationships of glycoprotein hormones; lessons from mutations and polymorphisms of the thyrotrophin and gonadotrophin subunit genes

“…The other two women detected with inactivating FSHâ mutation 27,28 were phenotypically very similar to the first case and all these findings agree as regards the crucial role of FSH in follicular maturation and ovarian oestrogen production. Very recently, a third woman with partial breast development and primary amenorrhoea was described, and she had a Tyr76 STOP mutation in the FSHâ gene 29 . The findings agree well with the observations in certain families from Finland, bearing the only so far known mutation that totally inactivates FSH receptor function 30,31 .…”