Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.

Détails

ID Serval
serval:BIB_A0F9A6C0CA8B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.
Périodique
Journal of Clinical Endocrinology and Metabolism
Auteur(s)
Beranova M., Oliveira L.M., Bédécarrats G.Y., Schipani E., Vallejo M., Ammini A.C., Quintos J.B., Hall J.E., Martin K.A., Hayes F.J., Pitteloud N., Kaiser U.B., Crowley W.F., Seminara S.B.
ISSN
0021-972X (Print)
ISSN-L
0021-972X
Statut éditorial
Publié
Date de publication
2001
Peer-reviewed
Oui
Volume
86
Numéro
4
Pages
1580-1588
Langue
anglais
Résumé
Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.
Mots-clé
Amino Acid Sequence/genetics, Animals, Base Sequence/genetics, COS Cells, Female, Gene Frequency, Genes, Recessive, Heterozygote, Homozygote, Humans, Hypogonadism/genetics, Hypogonadism/physiopathology, Male, Molecular Sequence Data, Mutation/genetics, Phenotype, Polymorphism, Genetic, Receptors, LHRH/genetics, Smell
Pubmed
Open Access
Oui
Création de la notice
03/12/2014 15:44
Dernière modification de la notice
20/08/2019 15:07
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