Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

Détails

ID Serval
serval:BIB_A51229A4D12D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.
Périodique
Proceedings of the National Academy of Sciences of the United States of America
Auteur⸱e⸱s
Sykiotis G.P., Plummer L., Hughes V.A., Au M., Durrani S., Nayak-Young S., Dwyer A.A., Quinton R., Hall J.E., Gusella J.F., Seminara S.B., Crowley W.F., Pitteloud N.
ISSN
1091-6490[electronic], 0027-8424[linking]
Statut éditorial
Publié
Date de publication
2010
Peer-reviewed
Oui
Volume
107
Numéro
34
Pages
15140-15144
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural Publication Status: ppublish
Résumé
Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
Mots-clé
Case-Control Studies, Cohort Studies, DNA Mutational Analysis, Extracellular Matrix Proteins/genetics, Female, Fibroblast Growth Factor 8/genetics, Gastrointestinal Hormones/genetics, Gene Regulatory Networks, Genetic Variation, Gonadotropin-Releasing Hormone/deficiency, Heterozygote, Homozygote, Humans, Hypogonadism/genetics, Kallmann Syndrome/genetics, Male, Models, Genetic, Mutation, Nerve Tissue Proteins/genetics, Neuropeptides/genetics, Pedigree, Phenotype, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptors, G-Protein-Coupled/genetics, Receptors, LHRH/genetics, Receptors, Peptide/genetics, Transcription Factors/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
09/03/2011 10:03
Dernière modification de la notice
20/08/2019 16:10
Données d'usage