Genotype and Phenotype of Patients with Gonadotropin-Releasing Hormone Receptor Mutations

Abstract

Human mutations in the gonadotropin releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.

A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred

“…In addition, the study by Maione reported an absence of radioiodinated GnRH signal in p.Thr269Met transfected COS‐7 cells compared to wild‐type GnRHR. Subsequent to 1997, several cases of normosmic CHH associated with GNRHR mutations have been reported …”

“…Subsequent to 1997, several cases of normosmic CHH associated with GNRHR mutations have been reported. 25,26 The GNRHR gene is located on the long arm of chromosome 4 (4q13.2) and consists of 3-exon gene spanning 18.7 kb that encodes a 328 amino acid protein. Inactivating mutations in GNRHR have been described in CHH patients with an autosomal recessive inheritance.…”

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

“…These three mutations are founder mutations, suggesting a hypothetical selective advantage for heterozygote carriers (Choi et al ., ). The Gln106Arg and Arg262Gln mutations account for approximately half of all reported mutant alleles (Kim et al ., ). In case of compound heterozygosity, one allele frequently carries either Gln106Arg or Arg262Gln.…”

A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

“…This variant appears most of the time in compound heterozygosity. However, three unrelated patients, two males and one female, have been reported to be homozygous for Q106R (14). All three patients display a mild phenotype, with a partial sexual development and for two of them, a spontaneous reversal of HH was reported.…”