Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

Détails

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Etat: Public
Version: Author's accepted manuscript
Licence: Non spécifiée
ID Serval
serval:BIB_DD27A8DA5823
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.
Périodique
Genetics In Medicine : Official Journal of the American College of Medical Genetics
Auteur(s)
Villanueva C., Jacobson-Dickman E., Xu C., Manouvrier S., Dwyer A.A., Sykiotis G.P., Beenken A., Liu Y., Tommiska J., Hu Y., Tiosano D., Gerard M., Leger J., Drouin-Garraud V., Lefebvre H., Polak M., Carel J.C., Phan-Hug F., Hauschild M., Plummer L., Rey J.P., Raivio T., Bouloux P., Sidis Y., Mohammadi M., de Roux N., Pitteloud N.
ISSN
1530-0366 (Electronic)
ISSN-L
1098-3600
Statut éditorial
Publié
Date de publication
11/2015
Peer-reviewed
Oui
Volume
17
Numéro
8
Pages
651-659
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.
METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays.
RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling.
CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.
Mots-clé
Adaptor Proteins, Signal Transducing/metabolism, Amino Acid Sequence, Animals, Conserved Sequence, Female, Genetic Association Studies, Humans, Hypogonadism/congenital, Hypogonadism/genetics, Limb Deformities, Congenital/genetics, Limb Deformities, Congenital/metabolism, MAP Kinase Signaling System, Male, Membrane Proteins/metabolism, Molecular Sequence Data, Mutation, Pedigree, Phosphorylation, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
03/12/2014 15:59
Dernière modification de la notice
20/08/2019 17:01
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