title: A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.
abstract: BACKGROUND
  The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH).
  
  
  OBJECTIVE
  The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood.
  
  
  METHODS
  In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood.
  
  
  RESULTS
  A new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up.
  
  
  CONCLUSIONS
  A novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.
authors.affiliation: The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Nimri
authors.forename: Yael
authors.initials: Y
authors.lastname: Lebenthal
authors.forename: Liora
authors.initials: L
authors.lastname: Lazar
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevrier
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.forename: Meytal
authors.initials: M
authors.lastname: Bar
authors.forename: Eva
authors.initials: E
authors.lastname: Hernandez-Mora
authors.forename: Nicolas
authors.initials: N
authors.lastname: de Roux
authors.forename: Galia
authors.initials: G
authors.lastname: Gat-Yablonski
mesh_terms: D000328:Adult; D019295:Computational Biology; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D005835:Genitalia / Q000473:pathology; D006062:Gonadotropins / Q000172:deficiency*; D006128:Growth / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D010641:Phenotype; D010902:Pituitary Gland / Q000000981:diagnostic imaging; D011627:Puberty / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed; D014162:Transfection; D055815:Young Adult
chemical_list: D006062:Gonadotropins; C118688:KISS1R protein, human; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D004247:DNA