Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia

Abstract

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.

Figure 1.

Pedigrees, haplotypes, and WNT10A mutation status of family 1 (A), family 2 (B), and family 3 (C). Individuals’ numbers are listed below the pedigree symbols. Genotyped markers from the chromosome 2q34-q36.2 region are shown to the left, and individuals’ allele numbers for each marker are given next to the bar. Black bars represent the haplotype segregating with the odonto-onycho-dermal gene. WNT10A is located between markers D2S2722 and rs1109867. The mutation genotypes of WNT10A are shown below haplotypes. + indicates mutation Glu233X; − indicates wild-type allele. A border indicates the common haplotype 1-C-3-3-4-T-1-T between the three families, and the arrow shows the neomutation in patient V:3 of family 3.

Figure 1.

Pedigrees, haplotypes, and WNT10A mutation status of family 1 (A), family 2 (B), and family 3 (C). Individuals’ numbers are listed below the pedigree symbols. Genotyped markers from the chromosome 2q34-q36.2 region are shown to the left, and individuals’ allele numbers for each marker are given next to the bar. Black bars represent the haplotype segregating with the odonto-onycho-dermal gene. WNT10A is located between markers D2S2722 and rs1109867. The mutation genotypes of WNT10A are shown below haplotypes. + indicates mutation Glu233X; − indicates wild-type allele. A border indicates the common haplotype 1-C-3-3-4-T-1-T between the three families, and the arrow shows the neomutation in patient V:3 of family 3.

Figure 1.

Pedigrees, haplotypes, and WNT10A mutation status of family 1 (A), family 2 (B), and family 3 (C). Individuals’ numbers are listed below the pedigree symbols. Genotyped markers from the chromosome 2q34-q36.2 region are shown to the left, and individuals’ allele numbers for each marker are given next to the bar. Black bars represent the haplotype segregating with the odonto-onycho-dermal gene. WNT10A is located between markers D2S2722 and rs1109867. The mutation genotypes of WNT10A are shown below haplotypes. + indicates mutation Glu233X; − indicates wild-type allele. A border indicates the common haplotype 1-C-3-3-4-T-1-T between the three families, and the arrow shows the neomutation in patient V:3 of family 3.

Figure 2.

WNT10A mutation associated with odonto-onycho-dermal dysplasia. Electropherograms of WNT10A exon 3 in a control individual (top), one parent (middle), and an affected patient (bottom). DNA sequence analysis revealed a homozygous G→T substitution at nucleotide 697 (from the translation start site) in the affected patient, causing the Glu233X mutation. The parent is heterozygous with respect to the Glu233X mutation.