Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.

Détails

ID Serval
serval:BIB_8D68D4FB3A2F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.
Périodique
Proceedings of the National Academy of Sciences of the United States of America
Auteur(s)
Pitteloud N., Zhang C., Pignatelli D., Li J.D., Raivio T., Cole L.W., Plummer L., Jacobson-Dickman E.E., Mellon P.L., Zhou Q.Y., Crowley W.F.
ISSN
0027-8424 (Print)
ISSN-L
0027-8424
Statut éditorial
Publié
Date de publication
2007
Peer-reviewed
Oui
Volume
104
Numéro
44
Pages
17447-17452
Langue
anglais
Notes
Publication types: Journal Article
Résumé
Gonadotropin-releasing hormone (GnRH) deficiency in the human presents either as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or with anosmia [Kallmann syndrome (KS)]. To date, several loci have been identified to cause these disorders, but only 30% of cases exhibit mutations in known genes. Recently, murine studies have demonstrated a critical role of the prokineticin pathway in olfactory bulb morphogenesis and GnRH secretion. Therefore, we hypothesize that mutations in prokineticin 2 (PROK2) underlie some cases of KS in humans and that animals deficient in Prok2 would be hypogonadotropic. One hundred IHH probands (50 nIHH and 50 KS) with no known mutations were examined for mutations in the PROK2 gene. Mutant PROK2s were examined in functional studies, and the reproductive phenotype of the Prok2(-/-) mice was also investigated. Two brothers with KS and their sister with nIHH harbored a homozygous deletion in the PROK2 gene (p.[I55fsX1]+[I55fsX1]). Another asymptomatic brother was heterozygous for the deletion, whereas both parents (deceased) had normal reproductive histories. The identified deletion results in a truncated PROK2 protein of 27 amino acids (rather than 81 in its mature form) that lacks bioactivity. In addition, Prok2(-/-) mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Homozygous loss-of-function PROK2 mutations cause both KS and nIHH.
Mots-clé
Animals, Base Sequence, Cell Movement, Female, Gastrointestinal Hormones/deficiency, Gastrointestinal Hormones/genetics, Gene Deletion, Gene Expression Regulation, Genotype, Gonadotropin-Releasing Hormone/metabolism, Humans, Hypogonadism/genetics, Hypogonadism/metabolism, Kallmann Syndrome/genetics, Kallmann Syndrome/metabolism, Male, Mice, Mice, Knockout, Mutation/genetics, Neurons/cytology, Neurons/metabolism, Neuropeptides/deficiency, Neuropeptides/genetics, Pedigree, Phenotype, Reproduction
Pubmed
Création de la notice
03/12/2014 16:33
Dernière modification de la notice
03/03/2018 19:15
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