Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome

Abstract

Ellis-van Creveld syndrome (EvC) is an autosomal recessive skeletal dysplasia. Elsewhere, we described mutations in EVC in patients with this condition (Ruiz-Perez et al. 2000). We now report that mutations in EVC2 also cause EvC. These two genes lie in a head-to-head configuration that is conserved from fish to man. Affected individuals with mutations in EVC and EVC2 have the typical spectrum of features and are phenotypically indistinguishable.

Figure 1

Haplotype analysis of the consanguineous pedigree with the shortest region of homozygosity. Informative markers and haplotypes are shown from telomere to centromere beneath the affected individual and her parents, showing the region of homozygosity between D4S2375 and D4S2935. Analysis of the other six pedigrees places the centromeric limit for the gene locus at 164F16P2 (data not shown). The gene order between D4S2375 and 164F16P2 is also shown.

Figure 2

Identification of EVC2 mutations. For each mutation, mutant genomic sequence is shown above corresponding wild-type sequence. Numbering starts at the translation start site in AY185210. The first two mutations are a single-base deletion (exon 22) and a single-base insertion (exon 14) that rapidly introduce stop codons. 3660delC is the mutation in the pedigree in figure 1. The C1195T (exon 10) and C1855T (exon 12) transitions introduce stop codons. T848G (exon 7) results in arginine replacing an isoleucine residue. The five-nucleotide insertion, 198 insGGCGG in exon 1, was found in the Brazilian pedigree described by Oliveira da Silva et al. (1980).

Figure 3

Scale representation of the syntenic chromosomal region shared by human, mouse, and pufferfish at the Ellis-van Creveld locus. Orientation of the human short arm of chromosome 4 and mouse chromosome 5 is from telomere to centromere; Fugu scaffolds lack chromosomal assignation. The size of the syntenic region for each species appears in brackets, and genes are represented by full boxes above or below the line, depending on whether their direction of transcription is toward the centromere or telomere, respectively. CRMP1, the 3′ end of which overlaps with the 3′ end of EVC in human (Ruiz-Perez et al. 2000), is not in an equivalent position in pufferfish. The serine threonine kinase is not found in Fugu, and interrogation of the mouse and Fugu databases (DOE Joint Genome Institute; The Fugu Genomics Project) does not detect AC1 orthologues. NSG1 is a neuron-specific protein (Carlock et al. 1996), and STX18 is a member of the syntaxin family of protein receptors that are involved in vesicle docking (Hatsuzawa et al. 2000). This diagram is based on August 2002 data freeze of the human, mouse, and Fugu genome assemblies.