title: Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism.
abstract: The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.
authors.affiliation: Service de Génétique, Hôpital Necker, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Bonaventure
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
authors.forename: L
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: M
authors.initials: M
authors.lastname: Le Merrer
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: P
authors.initials: P
authors.lastname: Maroteaux
mesh_terms: D000130:Achondroplasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000000981:diagnostic imaging; D017931:DNA Primers; D005091:Exons; D005333:Fetus; D005346:Fibroblast Growth Factors; D006132:Growth Plate / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012867:Skin / Q000473:pathology; D013796:Thanatophoric Dysplasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3