title: Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1).
abstract: Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were identified in both subtypes. While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. Here, we report the identification of FGFR3 mutations in 25/26 TD cases. Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). Our results suggest that TD1 is a genetically homogeneous condition and give additional support to the view that newly created cysteine residues in the extracellular domain of the protein play a key role in the severity of the disease.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de I'Enfant INSERM U-393, CNRS ER 88, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
authors.forename: V
authors.initials: V
authors.lastname: el Ghouzzi
authors.forename: A L
authors.initials: AL
authors.lastname: Delezoide
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: J
authors.initials: J
authors.lastname: Bonaventure
mesh_terms: D001483:Base Sequence; D003545:Cysteine / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D006653:Histology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011505:Protein-Tyrosine Kinases; D011871:Radiology; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D013796:Thanatophoric Dysplasia / Q000235:genetics*
chemical_list: D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D003545:Cysteine