The WNT10A gene in ectodermal dysplasias and selective tooth agenesis

Abstract

Mutations in the WNT10A gene were first detected in the rare syndrome odonto-onycho-dermal dysplasia (OODD, OMIM257980) but have now also been found to cause about 35-50% of selective tooth agenesis (STHAG4, OMIM150400), a common disorder that mostly affects the permanent dentition. In our random sample of tooth agenesis patients, 40% had at least one mutation in the WNT10A gene. The WNT10A Phe228Ile variant alone reached an allele frequency of 0.21 in the tooth agenesis cohort, about 10 times higher than the allele frequency reported in large SNP databases for Caucasian populations. Patients with bi-allelic WNT10A mutations have severe tooth agenesis while heterozygous individuals are either unaffected or have a mild phenotype. Mutations in the coding areas of the WNT10B gene, which is co-expressed with WNT10A during odontogenesis, and the WNT6 gene which is located at the same chromosomal locus as WNT10A in humans, do not contribute to the tooth agenesis phenotype.

Keywords: WNT10A; WNT10B; WNT6; ectodermal dysplasia; gene mutations; selective tooth agenesis.

Figure 1

WNT10A mutations found in our tooth agenesis patient cohort; e4=exon4 of WNT10A, fs=frame shift, F=Phenylalanine, I=Isoleucine, W=Tryptophan, N=Asparagine, R=Arginine, V=Valine, M=Methionine, H=Histidine, C=Cysteine, G=Glycine, S=Serine.

Figure 2

Two pedigrees showing incomplete penetrance and variability of the phenotype depending on the number of WNT10A alleles affected. The fifth generation of the pedigree on the left is still too young for phenotype evaluation. An additional feature in this family is that the husband of the homozygous index patient (arrow) also carries the F228I variant, a 1 in 50 chance. The pedigree on the right also shows that two different tooth agenesis genes may contribute to the phenotypes, because the daughter has several missing teeth but no F228I mutation while her two homozygous brothers have severe tooth agenesis. F=Phenylalanine, I=Isoleucine