A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome.
Activating mutations of FGFR3, a negative regulator of bone growth, are well known to cause a variety of short-limbed bone dysplasias and craniosynostosis syndromes. We mapped the locus causing a novel disorder characterized by camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL syndrome) to chromosome 4p. Because this syndrome recapitulated the phenotype of the Fgfr3 knockout mouse, we screened FGFR3 and subsequently identified a heterozygous missense mutation that is predicted to cause a p.R621H substitution in the tyrosine kinase domain and partial loss of FGFR3 function. These findings indicate that abnormal FGFR3 signaling can cause human anomalies by promoting as well as inhibiting endochondral bone growth.
Toydemir
Reha M
RM
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Brassington
Anna E
AE
Bayrak-Toydemir
Pinar
P
Krakowiak
Patrycja A
PA
Jorde
Lynn B
LB
Whitby
Frank G
FG
Longo
Nicola
N
Viskochil
David H
DH
Carey
John C
JC
Bamshad
Michael J
MJ
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005385:Fingers / Q000002:abnormalities; D006312:Hearing Loss, Bilateral / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014034:Toes / Q000002:abnormalities
D004247:DNA; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3