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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Base Sequence
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Bone Diseases, Developmental / genetics*
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DNA / genetics
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Female
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Fingers / abnormalities
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Hearing Loss, Bilateral / genetics
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Hearing Loss, Sensorineural / genetics*
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Heterozygote
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Humans
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Male
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Mice
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Mice, Knockout
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Models, Molecular
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Molecular Sequence Data
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Mutation, Missense*
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Pedigree
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Phenotype
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Protein Structure, Tertiary
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Receptor, Fibroblast Growth Factor, Type 3 / chemistry
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Receptor, Fibroblast Growth Factor, Type 3 / deficiency
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Receptor, Fibroblast Growth Factor, Type 3 / genetics*
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Sequence Homology, Amino Acid
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Syndrome
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Toes / abnormalities
Substances
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DNA
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FGFR3 protein, human
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Fgfr3 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 3
Associated data
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OMIM/100800
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OMIM/146000
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OMIM/147670
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OMIM/149730
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OMIM/187600
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OMIM/194190
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OMIM/602849
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RefSeq/NM_000142