Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation.
CONTEXT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). OBJECTIVE: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3548821?pdf=render |
id |
doaj-40b7198a37f6439d9dc1cd1d50c97c53 |
---|---|
record_format |
Article |
spelling |
doaj-40b7198a37f6439d9dc1cd1d50c97c532020-11-24T21:26:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0181e5389610.1371/journal.pone.0053896Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation.Frédéric BrioudeJérôme BouligandBruno FrancouJérôme FagartRonan RousselSay ViengchareunLaurent CombettesSylvie Brailly-TabardMarc LombèsJacques YoungAnne Guiochon-MantelCONTEXT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). OBJECTIVE: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation. RESULTS: An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 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 man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 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.http://europepmc.org/articles/PMC3548821?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Frédéric Brioude Jérôme Bouligand Bruno Francou Jérôme Fagart Ronan Roussel Say Viengchareun Laurent Combettes Sylvie Brailly-Tabard Marc Lombès Jacques Young Anne Guiochon-Mantel |
spellingShingle |
Frédéric Brioude Jérôme Bouligand Bruno Francou Jérôme Fagart Ronan Roussel Say Viengchareun Laurent Combettes Sylvie Brailly-Tabard Marc Lombès Jacques Young Anne Guiochon-Mantel Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. PLoS ONE |
author_facet |
Frédéric Brioude Jérôme Bouligand Bruno Francou Jérôme Fagart Ronan Roussel Say Viengchareun Laurent Combettes Sylvie Brailly-Tabard Marc Lombès Jacques Young Anne Guiochon-Mantel |
author_sort |
Frédéric Brioude |
title |
Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
title_short |
Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
title_full |
Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
title_fullStr |
Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
title_full_unstemmed |
Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
title_sort |
two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in kiss1r (kiss1 receptor): clinical evaluation and molecular characterization of a novel mutation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
CONTEXT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). OBJECTIVE: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation. RESULTS: An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 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 man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 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. |
url |
http://europepmc.org/articles/PMC3548821?pdf=render |
work_keys_str_mv |
AT fredericbrioude twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT jeromebouligand twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT brunofrancou twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT jeromefagart twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT ronanroussel twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT sayviengchareun twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT laurentcombettes twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT sylviebraillytabard twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT marclombes twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT jacquesyoung twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation AT anneguiochonmantel twofamilieswithnormosmiccongenitalhypogonadotropichypogonadismandbiallelicmutationsinkiss1rkiss1receptorclinicalevaluationandmolecularcharacterizationofanovelmutation |
_version_ |
1725978799321907200 |