Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)

Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia withmicromelic shortening of the limbs, macrocephaly, platyspondyly and reducedthoracic cavity. In the most common subtype (TD1), femurs are curved, whilein TD2, straight femurs are associated with cloverleaf skull. Mutations inthe fibroblast growth factor receptor 3 (FGFR3) gene were identified inboth subtypes. While TD2 was accounted for by a single recurrent mutationin the tyrosine kinase 2 domain, TD1 resulted from either stop codonmutations 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 and1/26 TD1 cases respectively. Both mutations created cysteine residues inthe juxta extramembrane domain of the receptor. Sixteen cases carried thepreviously reported R248C (9/26 cases), S249C (2/26 cases) or stop codonFGFR3 mutations (5/26 cases). Our results suggest that TD1 is a geneticallyhomogeneous condition and give additional support to the view that newlycreated cysteine residues in the extracellular domain of the protein play akey role in the severity of the disease.