title: Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.
abstract: The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop. Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia. In 90 individuals with suspected clinical diagnoses of hypochondroplasia who do not have Asn540Lys mutations, we screened for mutations, in FGFR3 exon 15, that would disrupt a unique BbsI restriction site that includes the Lys650 codon. We report here the discovery of three novel mutations (G1950T and G1950C [both resulting in Lys650Asn] and A1948C [Lys650Gln]) occurring in six individuals from five families. Several physical and radiological features of these individuals were significantly milder than those in individuals with the Asn540Lys mutations. The Lys650Asn/Gln mutations result in constitutive activation of the FGFR3 tyrosine kinase but to a lesser degree than that observed with the Lys540Glu and Lys650Met mutations. These results demonstrate that different amino acid substitutions at the FGFR3 Lys650 codon can result in several different skeletal dysplasia phenotypes.
authors.affiliation: Department of Dermatology, University of Colorado School of Medicine, Denver, CO 80262, USA. gary.bellus@uchsc.edu
authors.forename: G A
authors.initials: GA
authors.lastname: Bellus
authors.forename: E B
authors.initials: EB
authors.lastname: Spector
authors.forename: P W
authors.initials: PW
authors.lastname: Speiser
authors.forename: C A
authors.initials: CA
authors.lastname: Weaver
authors.forename: A T
authors.initials: AT
authors.lastname: Garber
authors.forename: C R
authors.initials: CR
authors.lastname: Bryke
authors.forename: J
authors.initials: J
authors.lastname: Israel
authors.forename: S S
authors.initials: SS
authors.lastname: Rosengren
authors.forename: M K
authors.initials: MK
authors.lastname: Webster
authors.forename: D J
authors.initials: DJ
authors.lastname: Donoghue
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001827:Body Height; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000503:physiopathology; D002348:Carpal Bones / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics*; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008239:Lysine / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D008239:Lysine