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), 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.
Dodé
Catherine
C
Institut Cochin, Inserm U567, Université René Descartes, Paris, France. catherine.dode@cch.aphop-paris.fr
Fouveaut
Corinne
C
Mortier
Geert
G
Janssens
Sandra
S
Bertherat
Jérôme
J
Mahoudeau
Jacques
J
Kottler
Marie-Laure
ML
Chabrolle
Christine
C
Gancel
Antoine
A
François
Inge
I
Devriendt
Koen
K
Wolczynski
Slawomir
S
Pugeat
Michel
M
Pineiro-Garcia
Alfons
A
Murat
Arnaud
A
Bouchard
Philippe
P
Young
Jacques
J
Delpech
Marc
M
Hardelin
Jean-Pierre
JP
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*
D020033:Protein Isoforms; D051496:Receptor, Fibroblast Growth Factor, Type 1