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

Dode, C; Fouveaut, C; Mortier, G; Janssens, S; Bertherat, J; Mahoudeau, J; Kottler, ML; Chabrolle, C; Gancel, A; Francois, Inge; Devriendt, Koenraad; Wolczynski, S; Pugeat, M; Pineiro-Garcia, A; Murat, A; Bouchard, P; Young, J; Delpech, M; Hardelin, JP

doi:10.1002/humu.9470

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

Author:

Dode, C

Fouveaut, C ; Mortier, G ; Janssens, S ; Bertherat, J ; Mahoudeau, J ; Kottler, ML ; Chabrolle, C ; Gancel, A ; Francois, Inge ; Devriendt, Koenraad ; Wolczynski, S ; Pugeat, M ; Pineiro-Garcia, A ; Murat, A ; Bouchard, P ; Young, J ; Delpech, M ; Hardelin, JP

Keywords:

DNA Mutational Analysis, Female, Genetic Testing, Humans, Kallmann Syndrome, Male, Morphogenesis, Mutation, Olfactory Bulb, Palate, Pedigree, Protein Isoforms, Receptor, Fibroblast Growth Factor, Type 1, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity, 3105 Genetics, 3202 Clinical sciences

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.