Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism

J Clin Endocrinol Metab. 2005 Mar;90(3):1849-55. doi: 10.1210/jc.2004-1418. Epub 2004 Dec 14.

Abstract

It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR)54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Female
  • Genetic Testing
  • Humans
  • Hypogonadism / epidemiology
  • Hypogonadism / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Receptors, Neuropeptide / genetics*

Substances

  • KISS1R protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Receptors, Neuropeptide