A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome

Abstract

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.

Figure  1.

Pedigree of the family with CATSHL syndrome. Filled symbols indicate either affected individuals (black) or individuals of unknown status (gray), and open symbols indicate unaffected individuals. Genotypes for D4S3038, D4S43, D4S127, and D4S412 are listed, and the disease haplotype segregating with each affected individual is boxed. The height (in centimeters) of each affected adult is indicated in italics.

Figure  2.

Clinical characteristics of CATSHL syndrome. A, Tall stature, pectus excavatum, and scoliotic deformity of the spine. Camptodactyly of the hands (B and C) and feet (D and E). F, Anterior-posterior radiograph of the thoracolumbar spine, showing ∼80° lateral curvature of the lumbar spine. G, Radiograph of the hand of an individual with camptodactyly.

Figure  3.

Representative audiograms of two individuals with CATSHL syndrome that demonstrate sensorineural hearing loss. Pure-tone response in the left ear is indicated by a cross (×) and response in the right ear by an open circle (○). Responses in the 500–8,000 Hz range were obtained in the mild sloping to severe hearing loss range, bilaterally.

Figure  4.

Identification of loss-of-function mutation in FGFR3 that causes CATSHL syndrome. A, A heterozygous G→A FGFR3 mutation creates a novel DraIII restriction site. B, Restriction digest with DraIII that confirmed homozygosity for the uncut wild-type FGFR3 allele (419 bp) in unaffected individuals (open symbols), whereas affected individuals (filled symbols) were heterozygous for a wild-type allele (419 bp) and a mutant allele that cut into two fragments (318 and 101 bp). C, Amino acid alignment of different FGFRs. Arginine at codon 621 of the activation domain is conserved among human FGFR1, -2, -3, and -4 (top), in all vertebrate FGFR3s characterized to date (middle), and in other receptor tyrosine kinases (bottom).

Figure  5.

A, Ball-and-stick model of the active-site region of the catalytic domain of FGFR1. The model is based on the 0.2-nm crystal structure of the tyrosine kinase domain of the human FGFR1 (RSCB Protein Data Bank entry 1FGK). R627 of FGFR1 is homologous to R621 of FGFR3. B, Hypothetical model of FGFR3, showing position of histidine side chain when substituted for R621.