title: Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis.
abstract: 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.
authors.affiliation: Institut Cochin, Inserm U567, Université René Descartes, Paris, France. catherine.dode@cch.aphop-paris.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Corinne
authors.initials: C
authors.lastname: Fouveaut
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Jacques
authors.initials: J
authors.lastname: Mahoudeau
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Kottler
authors.forename: Christine
authors.initials: C
authors.lastname: Chabrolle
authors.forename: Antoine
authors.initials: A
authors.lastname: Gancel
authors.forename: Inge
authors.initials: I
authors.lastname: François
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Slawomir
authors.initials: S
authors.lastname: Wolczynski
authors.forename: Michel
authors.initials: M
authors.lastname: Pugeat
authors.forename: Alfons
authors.initials: A
authors.lastname: Pineiro-Garcia
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouchard
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Marc
authors.initials: M
authors.lastname: Delpech
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D009830:Olfactory Bulb / Q000196:embryology*; D010159:Palate / Q000196:embryology*; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D051496:Receptor, Fibroblast Growth Factor, Type 1