Abstract
Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth1,2. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil3. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region4. We have identified a new gene (EVC), encoding a 992–amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.
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References
Ellis, R.W.B. & van Creveld, S. A syndrome characterised by ectodermal dysplasia, polydactyly, chondrodysplasia and congenital morbus cordis: report of three cases. Arch. Dis. Child. 15 , 65–84 (1940).
McKusick, V.A., Egeland, J.A., Eldridge, R. & Krusen, D.E. Dwarfism in the Amish I. The Ellis-van Creveld Syndrome. Bull. Johns Hopkins Hosp. 115, 306–336 (1964).
Polymeropoulos, M.H. et al. The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16. Genomics 35, 1– 5 (1996).
Howard, T.D. et al. Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus. Am. J. Hum. Genet. 61, 1405–1412 (1997).
Ide, S.E., Ortiz de Luna, R.I., Francomano, C.A. & Polymeropoulos, M.H. Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish. Hum. Genet. 98, 572 –575 (1996).
Spranger, S. & Tariverdian, G. Symptomatic heterozygosity in the Ellis-van Creveld syndrome? Clin. Genet. 47, 217–220 (1995).
Digilio, M.C., Marino, B., Giannotti, A. & Dallapiccola, B. Single atrium, atrioventricular canal/postaxial hexodactyly indicating Ellis-van Creveld syndrome. Hum. Genet. 96, 251– 253 (1996).
Krawczak, M. & Cooper, D.N. The human gene mutation database. Trends Genet. 13, 121– 122 (1997).
Ishida, Y. et al. Isolation and characterisation of 21 novel expressed DNA sequences from the distal region of human chromosome 4p. Genomics 22, 302–312 (1994).
Wilson, G.M. et al. Regulation of AUF1 expression via conserved alternatively spliced elements in the 3′ untranslated region. Mol. Cell. Biol. 6, 4056–4064 ( 1999).
Petrukhin, K. et al. Identification of the gene responsible for Best macular dystrophy . Nature Genet. 3, 241– 247 (1998).
Ubeda, M., Schmitt-Ney, M., Ferrer, J. & Habener, J.F. CHOP/GADD153 and the methionyl-tRNA synthetase (MetRS) genes overlap in a conserved region that controls mRNA stability. Biochem. Biophys. Res. Commun. 19, 31–38 ( 1999).
Hill, R.D. Two cases of Ellis-van Creveld syndrome in a small island population. J. Med. Genet. 14, 33–36 (1977).
Bullen, P. & Wilson, D.I. The Carnegie staging of human embryos: a practical guide. in Molecular Genetics of Early Human Development (eds Strachan, T., Lindsay, S. & Wilson, D.I.) 27– 35 (Bios Scientific, Oxford, 1997).
Hanley, N.A. et al. Expression of steroidogenic factor 1 and Wilms′ tumour 1 during early human gonadal development and sex determination. Mech. Dev. 87, 175–180 ( 1999).
Acknowledgements
We thank A. Verloes, A. Nerlich and I. Young for sending samples from patients, and J. Burn and T. Strachan for encouragement. This work was supported by the British Heart Foundation, Newcastle Hospital Special Trustees, the Knott Trust, the Borwick Trust and the Deutsche Forschungsgemeinschaft.
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Ruiz-Perez, V., Ide, S., Strom, T. et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24, 283–286 (2000). https://doi.org/10.1038/73508
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DOI: https://doi.org/10.1038/73508
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