A new gene, EVC2, is mutated in Ellis–van Creveld syndrome

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Abstract

Ellis–van Creveld syndrome (EvC; MIM 225500) is an autosomal recessive chondrodysplastic dwarfism. Thus far, the identified mutations in the EVC gene located on chromosome 4p16 have only accounted for illness in a small proportion of affected individuals. In this report we describe a novel gene, EVC2, that is mutated in an Ashkenazi individual with EvC syndrome. Our findings demonstrate for the first time that the heterogeneity observed in this disorder is not solely the result of mutations in a single gene.

Introduction

Ellis–van Creveld syndrome [1], [2], [3] is an autosomal recessive chondrodysplastic dwarfism frequently associated with congenital heart disease. The clinical manifestations of EvC syndrome often include short-limbed dwarfism, short ribs, postaxial polydactyly, and dysplastic nails and teeth [1], [2]. Mutations in the EVC gene on chromosome 4p16 [4], [5] were first reported in individuals with EvC in the Old Order Amish and other cases from Mexico, Equador, and Brazil [6]. However, mutations in the EVC gene have not yet been identified in a significant number of affected individuals [7]. Thus, we hypothesized that mutations in genes contiguous to EVC, such as CRMP-1 [8] might be associated with the clinical manifestations observed in EvC, including the congenital cardiac atrial-septal defects that occur in approximately 60% of affected individuals. Sequence analysis did not reveal any changes in the coding region of CRMP-1 that were associated with EvC. However, in the region 5 to EVC we identified a novel gene that is mutated in an Ashkenazi child with EvC.

Section snippets

Patient and control samples

The patient’s family (Fig. 1) is of Ashkenazi Jewish origin, and includes the unaffected parents (B110 and B111), unaffected siblings (B101 through B109), and a deceased affected sibling (DNA not available). The living affected child has typical features of EvC, including late remaining baby teeth, displaced mature teeth, an extra finger that was removed, absent fingernails, and a heart murmur. Control Ashkenazi Jewish DNA samples (n=319) were also genotyped. All samples were drawn under

Results and discussion

The new gene, EVC2, spans 166.4 kb, is divergent to, and shares a common promoter region with EVC. Sequence analysis of this promotor region identified several potential transcription factor binding sites including Sp1, AP-2, myogenin, and C/EBP (data not shown) [10]. This organization of these two adjacent genes suggests that they may be transcribed in a coordinated fashion and therefore they may be functionally related. The transcriptional start sites of EVC and EVC2 are separated by only 1643 

Acknowledgements

We thank the patients and family members who participated in this study. We are also grateful to Rabbi Joseph Ekstein and Dor Yeshorum for their help in making this work possible. The helpful discussions with Drs. Ethylin W. Jabs and Brian Martin were greatly appreciated.

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