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

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.

[1]  D. Rimoin,et al.  Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3 , 1995, Nature Genetics.

[2]  Joseph Schlessinger,et al.  Signal transduction by receptors with tyrosine kinase activity , 1990, Cell.

[3]  W. Reardon,et al.  Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes , 1995, Nature Genetics.

[4]  D. Rimoin,et al.  Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. , 1995, Human molecular genetics.

[5]  Sue Malcolm,et al.  Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome , 1994, Nature Genetics.

[6]  M. Golabi,et al.  Thanatophoric dysplasia and cloverleaf skull. , 1987, American journal of medical genetics. Supplement.

[7]  D. Church,et al.  Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia , 1994, Cell.

[8]  A. Ullrich,et al.  Stabilization of an active dimeric form of the epidermal growth factor receptor by introduction of an inter-receptor disulfide bond. , 1994, The Journal of biological chemistry.

[9]  H. Lodish,et al.  Homodimerization and constitutive activation of the erythropoietin receptor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[10]  I. Kaitila,et al.  A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia , 1995, Nature Genetics.

[11]  M. Altherr,et al.  Genomic organization of the mouse fibroblast growth factor receptor 3 (Fgfr3) gene. , 1995, Genomics.

[12]  Arnold Munnich,et al.  Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia , 1994, Nature.

[13]  E. Jabs,et al.  Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. , 1995, Human molecular genetics.

[14]  M. Eccles,et al.  Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2 , 1994, Nature Genetics.

[15]  A. Munnich,et al.  Stop codon FGFR3 mutations in thanatophoric dwarfism type 1 , 1995, Nature Genetics.