Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis

In a new cohort of 141 unrelated patients affected by Kallmann syndrome we identified FGFR1 sequence variants in 17 patients, all in the heterozygous state. The fifteen novel variants consist of 10 missense (p.N77K, p.C101F, p.R250W, p.G270D, p.P283R, p.S332C, p.H621R, p.S685F, p.I693F, p.R822C), tw...

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Published in:Human mutation 2007-01, Vol.28 (1), p.97-98
Main Authors: Dodé, Catherine, Fouveaut, Corinne, Mortier, Geert, Janssens, Sandra, Bertherat, Jérôme, Mahoudeau, Jacques, Kottler, Marie-Laure, Chabrolle, Christine, Gancel, Antoine, François, Inge, Devriendt, Koen, Wolczynski, Slawomir, Pugeat, Michel, Pineiro-Garcia, Alfons, Murat, Arnaud, Bouchard, Philippe, Young, Jacques, Delpech, Marc, Hardelin, Jean-Pierre
Format: Article
Language:English
Subjects:
alternative splicing
anosmia
bimanual synkinesis
cleft palate
DNA Mutational Analysis
Female
FGFR1c
Genetic Testing
Humans
hypogonadotropic hypogonadism
Kallmann syndrome
Kallmann Syndrome - genetics
Male
Morphogenesis - genetics
Mutation
Olfactory Bulb - embryology
Palate - embryology
Pedigree
Protein Isoforms - genetics
Protein Isoforms - physiology
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Receptor, Fibroblast Growth Factor, Type 1 - physiology
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Summary:In a new cohort of 141 unrelated patients affected by Kallmann syndrome we identified FGFR1 sequence variants in 17 patients, all in the heterozygous state. The fifteen novel variants consist of 10 missense (p.N77K, p.C101F, p.R250W, p.G270D, p.P283R, p.S332C, p.H621R, p.S685F, p.I693F, p.R822C), two nonsense (p.E324X, p.R661X), a frameshift (p.S439fs), and two splice site (c.1081G>C and c.1977+1G>A) changes. However, the p.N77K and p.R822C changes were also found in two and one out of 150 healthy control individuals, respectively, and therefore, their pathogenic effect is questionable. Notably, three alterations (p.E324X, p.S332C, c.1081G>C) are located in the alternative exon 8B that codes for the FGFR1c isoform, thus indicating that this isoform plays a crucial role in the development of the olfactory system in man. Moreover, the presence of cleft palate in a patient carrying the p.E324X change shows that FGFR1c is important for palate morphogenesis too. © 2006 Wiley‐Liss, Inc.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.9470