Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations
| Autor: | Michel Polak, Carine Villanueva, Lacey Plummer, Franziska Phan-Hug, Michael Hauschild, Juliane Léger, Cheng Xu, Yisrael Sidis, Nelly Pitteloud, Taneli Raivio, Hervé Lefebvre, Elka Jacobson-Dickman, Jean-Claude Carel, Moosa Mohammadi, Dov Tiosano, Sylvie Manouvrier, Gerasimos P. Sykiotis, Pierre Bouloux, Jean-Pierre Rey, Valérie Drouin-Garraud, Youli Hu, Andrew A. Dwyer, Yang Liu, Andrew Beenken, Nicolas de Roux, Johanna Tommiska, Marion Gérard |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Proband
Male medicine.medical_specialty Kallmann syndrome MAP Kinase Signaling System Population Molecular Sequence Data Limb Deformities Congenital Biology medicine.disease_cause Article congenital hypogonadotropic hypogonadism 03 medical and health sciences Internal medicine medicine Animals Humans Amino Acid Sequence Receptor Fibroblast Growth Factor Type 1 Phosphorylation education Genetics (clinical) Conserved Sequence Genetic Association Studies 030304 developmental biology Genetic testing Adaptor Proteins Signal Transducing 0303 health sciences education.field_of_study Mutation medicine.diagnostic_test fibroblast growth factor receptor 1 Fibroblast growth factor receptor 1 FGF receptor substrate 2α Hypogonadism 030305 genetics & heredity Membrane Proteins Micropenis medicine.disease 3. Good health Pedigree Endocrinology split hand/foot malformation Female Congenital Hypogonadotropic Hypogonadism Adaptor Proteins Signal Transducing/metabolism Hypogonadism/congenital Hypogonadism/genetics Limb Deformities Congenital/genetics Limb Deformities Congenital/metabolism Membrane Proteins/metabolism Receptor Fibroblast Growth Factor Type 1/genetics Receptor Fibroblast Growth Factor Type 1/metabolism |
| Zdroj: | Genetics In Medicine : Official Journal of the American College of Medical Genetics, vol. 17, no. 8, pp. 651-659 Genetics in medicine : official journal of the American College of Medical Genetics |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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