Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.
Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
de Roux
Nicolas
N
Institut National de la Santé et de la Recherche Médicale Unité 135, Unité de Recherches Hormones Gènes et Reproduction, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France. deroux@necker.fr
Genin
Emmanuelle
E
Carel
Jean-Claude
JC
Matsuda
Fumihiko
F
Chaussain
Jean-Louis
JL
Milgrom
Edwin
E
D001483:Base Sequence; D003241:Consanguinity; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000502:physiology
D017931:DNA Primers; C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide