| Ellis-van Creveld syndrome (EvC) is an autosomal recessive chondrodysplastic dwarfism frequently associated with congenital heart disease. The clinical manifestations commonly observed in EvC include short-limbed, disproportionate dwarfism, post-axial polydactyly, and dysplasia of fingernails and teeth (69). In this work, we have: (a) refined the extent of the EvC syndrome locus on chromosome 4p16; (b) identified and characterized two genes, EVC and CEL300 at this locus; and, (c) discovered mutations in these genes that co-segregate with the EvC syndrome in patients.; The EVC gene extends over a 117.1 kb, contains 21 coding exons, has four transcription start sites defining alternative exons 1, and has three alternate 3′ untranslated regions. The CEL300 gene spans 166.4 kb, contains three alternative transcription start sites, and generates transcripts of 22 or 23 exons due to alternative 3′ untranslated regions. The EVC and CEL300 genes are divergently transcribed and share a common promoter region. This promoter region contains several transcription factor binding sites, which are possibly shared by the two genes. The unusual organization of these two adjacent genes suggests that they may be transcribed in a coordinated fashion and therefore they may also be functionally related. Sequencing of the coding regions, 5′ and 3′ regions, and a common promoter region of the EVC and CEL300 genes in samples from controls and patients showed that the mutation in EVC gene correlates with the EvC syndrome in the Old Order Amish pedigree of Lancaster, Pennsylvania; while mutations in the CEL300 gene are associated with the EvC syndrome in an Ashkenazi Jewish family. Future studies of both the EVC and CEL300 genes should lead to a better understanding of the pathogenesis and clinical spectrum of not only Ellis-van Creveld syndrome, but also other skeletal. In addition, the finding that mutations in either the EVC or CEL300 gene result in Ellis-van Creveld syndrome adds another dimension to not only the clinical diagnosis of EvC but also to the interpretation of genetic information used for prenatal diagnosis and genetic counseling. |
