ECE2013 Poster Presentations Male reproduction (41 abstracts)
KISS1R mutations in normosmic congenital hypogonadotropic hypogonadism: clinical evaluation of two families and molecular characterization of a novel mutation
Frederic Brioude 1, , Jerome Bouligand 2, , Bruno Francou 2, , Jerome Fagart 4, , Ronan Roussel 7 , Say Viengchareun 4, , Laurent Combettes 8 , Sylvie Brailly-Tabard 2, , Marc Lombes 4, , Jacques Young 3, & Anne Guiochon-Mantel 2,
1APHP Hopital Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France; 2APHP, Hopital Bicetre, Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Paris, France; 3APHP, Hopital Bicetre, Service d’Endocrinologie et des Maladies de la Reproduction, Paris, France; 4Univ Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin Bicetre, France; 5Univ Pierre et Marie Curie, Paris, France; 6Inserm UMR-S693, Le Kremlin Bicetre, France; 7APHP, Hopital Bichat, Unite de Diabetologie, Paris, France; 8Inserm U757, Orsay, France.
Context: KISS1R mutations have been implicated in patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).
Objective: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to two unrelated families, and to functionally characterize a novel KISS1R mutation.
Results: The p.Tyr313His original mutant was found in the homozygous state in three affected kindred (two females and one male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this patient, pulsatile GnRH administration restored pulsatile LH secretion and testicular hormone secretion, and long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in two miscarriages and the birth of a healthy boy.
Conclusion: We show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH. The possible role of KISS1R haploinsufficiency in miscarriage is discussed.
Volume 32
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Endocrine Abstracts
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