HGNC Approved Gene Symbol: WNT10A
SNOMEDCT: 403762003, 700062000;
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:218,874,116-218,893,928 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Ectodermal dysplasia 16 (odontoonychodermal dysplasia) | 257980 | Autosomal recessive | 3 |
| Schopf-Schulz-Passarge syndrome | 224750 | Autosomal recessive | 3 | |
| Tooth agenesis, selective, 4 | 150400 | Autosomal dominant; Autosomal recessive | 3 |
The WNT gene family consists of structurally related genes encoding secreted signaling molecules that have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. For general information about WNT genes, see WNT1 (164820).
By searching for sequences homologous to the mouse Wnt10b sequence (601906), Kirikoshi et al. (2001) identified WNT10A in human chromosome 2 draft sequence and assembled a cDNA sequence using PCR techniques. WNT10A encodes a deduced 417-amino acid peptide containing residues conserved among WNTs and 2 N-linked glycosylation sites. WNT10A shares 59.2% amino acid sequence identity with human WNT10B. Using Northern blot analysis, Kirikoshi et al. (2001) detected 3.0- and 2.4-kb WNT10A transcripts at moderate levels in fetal kidney, placenta, and adult spleen and at low levels in fetal lung, adult kidney, prostate, and ovary. They detected WNT10A overexpression in human cancer cell lines, including HL-60 (promyelocytic leukemia), Raji (Burkitt lymphoma), and SW480 (colorectal cancer), where it was coexpressed with WNT6 (604663). Kirikoshi et al. (2001) hypothesized that, like WNT1 and WNT10B, WNT10A and WNT6 may play key roles in human carcinogenesis.
Using sequence analysis, Kirikoshi et al. (2001) determined that the WNT10A gene contains 4 exons and is clustered with WNT6 (604663) in a head-to-tail manner with an interval of less than 7 kb.
Using genomic sequence analysis, Kirikoshi et al. (2001) mapped the WNT10A gene to chromosome 2q35 near the WNT6 gene.
Odontoonychodermal Dysplasia
Odontoonychodermal dysplasia (OODD; 257980) 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. Adaimy et al. (2007) studied 3 consanguineous Lebanese Muslim Shiite families that included 6 individuals affected with OODD. Screening of genes within the candidate region on chromosome 2q35-q36.2 led to identification of the same homozygous glu233-to-stop nonsense mutation in exon 3 of the WNT10A gene (606268.0001) in all patients. The authors stated that this was the first report of a human phenotype resulting from a mutation in WNT10A, and the first demonstration of an ectodermal dysplasia (ED) caused by an altered WNT signaling pathway.
In 12 patients from 11 unrelated families of German and Turkish origin with ectodermal dysplasia, who were known to be negative for mutation in the ectodysplasin-A gene (EDA; 300451), Bohring et al. (2009) identified homozygosity or compound heterozygosity for 3 missense and 2 nonsense mutations in the WNT10A gene (606268.0002-606268.0006, respectively). A brother and sister from 1 family had oligodontia and sparse body hair and eyebrows as their only manifestations (STHAG4; 150400), and a female proband from another family had cysts of the eyelids in addition to hypodontia, hypotrichosis, palmoplantar keratosis, and dystrophic nails (SSPS; 224750). Despite the high degree of variability in phenotypic expression, Bohring et al. (2009) stated that there was no recognizable genotype/phenotype correlation.
In 2 Indian sibs with OODD, Xu et al. (2017) identified homozygosity for a splice site mutation in the WNT10A gene (606268.0010). Both parents were heterozygous for the mutation.
By sequencing the WNT10A gene in 4 unrelated patients with a clinical diagnosis of OODD, Yu et al. (2019) identified 5 novel mutations in the WNT10A gene (see, e.g., 606268.0011-606268.0013). The mutations segregated with the disorder in the families for which parental DNA was available for testing.
Selective Tooth Agenesis 4
In an American family with variable hypodontia involving the lateral incisors and premolar teeth (STHAG4; 150400), Kantaputra and Sripathomsawat (2011) analyzed the candidate gene WNT10A and identified 2 different missense mutations, F228I (606268.0003) and D217N (606268.0007), for which affected members were heterozygous or compound heterozygous. None of the family members had other manifestations of ectodermal dysplasia.
Van den Boogaard et al. (2012) identified WNT10A mutations in 19 (56%) of 34 unrelated patients with nonsyndromic tooth agenesis (see, e.g., 606268.0002-606268.0004), 8 of whom were homozygous, 4 compound heterozygous, and 7 heterozygous for the mutations. The most frequent mutation, F228I (606268.0003), represented 62% of the WNT10A mutations in these nonsyndromic hypodontia patients, a frequency that was significantly higher (OR, 17.9; p less than 0.05) than the frequency of F228I observed in unselected controls (2.3%). The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Van den Boogaard et al. (2012) also identified homozygosity, heterozygosity, or compound heterozygosity for the C107X (606268.0002) and F228I mutations in 11 patients with tooth agenesis who had mild features of ectodermal dysplasia, but did not exhibit the characteristic features of OODD. Overall, no specific pattern of tooth agenesis was observed for WNT10A mutation carriers.
In 16 probands with features of ectodermal dysplasia referred with tooth agenesis and features of ED, Plaisancie et al. (2013) identified heterozygosity, homozygosity, or compound heterozygosity for mutations in WNT10A. The C107X and F228I mutations represented 43% and 18% of the detected WNTA10A variants, respectively. The authors observed associated features of ED in 15 of the 16 patients with WNT10A mutations; noting that ED features were present in only 11 of the 30 patients studied by van den Boogaard et al. (2012), Plaisancie et al. (2013) suggested that this reflected different methods of recruitment.
In a population-based cohort of 94 Swedish families including 102 individuals with nonsyndromic tooth agenesis (mean of 8.2 missing teeth), Arzoo et al. (2014) identified 26 probands (27.7%) with mutation in the WNT10A gene, 17 of whom had monoallelic mutations and 11 biallelic mutations. Individuals with biallelic mutations had a higher number of missing teeth (mean, 11.1) than did those with monoallelic mutations (mean, 6.8). Upper and lower premolars were the most common type of missing teeth (59.7% of all missing teeth). Probands with biallelic mutations had a higher frequency of absent maxillary and mandibular molars (p = 3.63 x 10(-6)) and mandibular central incisors (p = 6.91 x 10(-3)). There were no differences in type or number of missing teeth between males and females.
In 6 of 9 unrelated Thai patients with agenesis or isolated hypodontia of the maxillary permanent canines, Kantaputra et al. (2014) identified 3 different heterozygous mutations in the WNT10A gene (see, e.g., 606268.0009). One of the affected individuals also had pegged maxillary permanent lateral incisors with dens invaginatus. Two mothers of the patients carried the mutation and had pegged maxillary permanent lateral incisors.
Yang et al. (2015) found that Wnt10a-null mice generated by the knockout mouse project (KOMP) exhibited supernumerary mandibular fourth molars, smaller molars with abnormal cusp patterning, root taurodontism, reduced volume of dentin, pulp calcification, molar crown dysmorphologies, and increased risk of root resorption following tooth development and eruption. The total tooth volume of the Wnt10a-null first mandibular molars averaged 71% of the wildtype. The enamel, dentin, and pulp volumes averaged 87%, 67%, and 84% of those of the wildtype molars, respectively.
Xu et al. (2017) generated a conditional Wnt10a knockout mouse and studied developmental and tissue specific functional roles of Wnt10a. Wnt10a-deficient mice exhibited region-specific tongue and palmoplantar abnormalities, decreased sweat duct basal proliferation, and decreased basal proliferation of fungiform and circumvallate taste buds. Xu et al. (2017) demonstrated that the absence of Wnt10a led to decreased activity in beta-catenin pathways and reduced adult epithelial progenitor cell proliferation. The authors concluded that WNT10A/beta-catenin signaling controls progenitor cell proliferation in diverse epithelia.
In affected members from 3 families with odontoonychodermal dysplasia (OODD; 257980), Adaimy et al. (2007) demonstrated homozygosity for the same nonsense mutation in the WNT10A gene. A 697G-T transversion in exon 3 causes substitution of a stop codon for the negatively charged glu233 (E233X), resulting in a prematurely truncated protein of 232 amino acids instead of 417 amino acids.
In affected members of 3 families with odontoonychodermal dysplasia (OODD; 257980) and 1 proband of a family with Schopf-Schulz-Passarge syndrome (SPSS; 224750), Bohring et al. (2009) identified homozygosity for a 321C-A transversion in the WNT10A gene, resulting in a cys107-to-ter (C107X) substitution that was not found in 200 control chromosomes. In 2 additional probands with OODD, the C107X mutation was found in compound heterozygosity with a phe228-to-ile (F228I; 606268.0003) mutation, and in a brother and sister who had oligodontia and sparse body hair and eyebrows as their only manifestations, the C107X mutation was found in compound heterozygosity with an arg128-to-gln (R128Q; 606268.0004) mutation. Of 18 heterozygous carriers of the C107X mutation, 10 exhibited some phenotypic manifestation, including anomalies of teeth, skin, and nails.
In 2 unrelated patients with nonsyndromic tooth agenesis (STHAG4; 150400), van den Boogaard et al. (2012) identified heterozygosity for the C107X mutation in the WNT10A gene; in 3 other patients, the mutation was present in compound heterozygosity with the F228I mutation. In addition, van den Boogaard et al. (2012) identified mutations in the C107X mutation in 6 patients with tooth agenesis who had mild features of ectodermal dysplasia, but who did not exhibit the characteristic features of OODD; 2 were heterozygous, 1 was homozygous, and 3 were compound heterozygous for C207X and F228I.
In 4 probands with tooth agenesis and features of ectodermal dysplasia, Plaisancie et al. (2013) identified the C107X mutation in the WNT10A gene, present in homozygosity in 1 patient and in compound heterozygosity in 3 patients, including with the F228I mutation in 1 proband. In the latter family, the proband's unaffected father and mother were each heterozygous for 1 of the mutations.
In 2 probands with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 682T-A transversion in the WNT10A gene, resulting in a phe228-to-ile (F228I) substitution at an evolutionarily conserved residue. In 2 additional probands with OODD, the F228I mutation was found in compound heterozygosity with the C107X mutation (606268.0002). The F228I mutation was not found in 200 control chromosomes. Of 15 heterozygous carriers of the F228I mutation, 7 exhibited some phenotypic manifestation, including anomalies of teeth, skin, hair, and nails.
In the affected father and eldest son from an American family with variable hypodontia involving lateral incisors and premolar teeth (STHAG4; 150400), Kantaputra and Sripathomsawat (2011) identified heterozygosity for the F228I mutation in the WNT10A gene. Another affected son, who had only microdontia of the left mandibular second premolar, was compound heterozygous for F228I and a 649G-A transition in exon 3 of the WNT10A gene, resulting in an asp217-to-asn (D217N; 606268.0007) substitution, which he had inherited from his unaffected mother, who had normal dentition. The D217N mutation was also present in heterozygosity in another affected son, who had absence of the maxillary permanent lateral incisors, mandibular second premolars, and a mandibular permanent lateral incisor. Examination of the family members revealed no other manifestations of ectodermal dysplasia. Neither mutation was found in 200 control chromosomes from individuals with normal dentition from a Thai DNA bank registry or in 400 Swedish and 400 Pakistani control chromosomes.
In 13 patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) identified the F228I mutation in the WNT10A gene; the mutation was homozygous in 7 patients, heterozygous in 2 patients, and compound heterozygous with C107X in 3 patients and with G95K (606268.0008) in 1 patient. The authors noted that F228I was found in unselected controls at an allele frequency of 2.3%, reflecting the high prevalence of tooth agenesis in the general population. In addition, van den Boogaard et al. (2012) identified heterozygosity, homozygosity, or compound heterozygosity for the F228I mutation in 8 patients with tooth agenesis who had mild features of ectodermal dysplasia, but did not exhibit the characteristic features of OODD; 2 were heterozygous, 2 were homozygous, 3 were compound heterozygous for C207X and F228I, and 1 was compound heterozygous for C208X and a W277C mutation in WNT10A.
In 8 probands with tooth agenesis, 7 of whom also exhibited features of ectodermal dysplasia, Plaisancie et al. (2013) identified the F228I mutation in the WNT10A gene, present in heterozygosity in 2 patients, in homozygosity in 3 patients, and in compound heterozygosity with another WNT10A variant in 3 patients. Of the 3 patients homozygous for F228I, 1 had severe tooth agenesis without other associated features, whereas the other 2 probands had tooth agenesis, conical teeth, and thin nails, as well as short stature in 1 of them and thick hair in the other.
In a population-based study of 102 Swedish individuals with nonsyndromic tooth agenesis, Arzoo et al. (2014) identified the F228I variant in the WNT10A gene as the most prevalent variant in their cohort. It represented 13.3% of all oligodontia alleles and was found in 21 of 94 probands.
In a brother and sister with odontoonychodermal dysplasia (OODD; 257980), who had oligodontia and sparse body hair and eyebrows as their only manifestations, Bohring et al. (2009) identified compound heterozygosity for a 383G-A transition in the WNT10A gene, resulting in an arg128-to-gln (R128Q) substitution at an evolutionarily conserved residue, and the C107X mutation (606268.0002). Of 2 family members who were heterozygous carriers of the R128Q mutation, 1 was noted to have sparse eyebrows. The R128Q mutation was found in 2 of 396 control chromosomes.
In a patient with nonsyndromic tooth agenesis (STHAG4; 150400), van den Boogaard et al. (2012) identified heterozygosity for the R128Q mutation in the WNT10A gene.
In 2 sisters with odontoonychodermal dysplasia (OODD; 257980), Bohring et al. (2009) identified homozygosity for a 1128C-A transversion in the WNT10A gene, resulting in a cys376-to-ter (C376X) substitution that was not found in 200 control chromosomes. Their unaffected father was a heterozygous carrier; their mother was deceased.
In a female proband with odontoonychodermal dysplasia (OODD; 257980), born of first-cousin parents, Bohring et al. (2009) identified homozygosity for a 27G-A transition in the WNT10A gene, resulting in a trp9-to-ter (W9X) substitution that was not found in 200 control chromosomes. Her parents and a maternal aunt, who were heterozygous for the mutation, had anomalies of the teeth, nails, and hair.
For discussion of the asp217-to-asn (D217N) mutation in the WNT10A gene that was found in compound heterozygous state in patients with variable hypodontia involving lateral incisors and premolar teeth (STHAG4; 150400) by Kantaputra and Sripathomsawat (2011), see 606268.0003.
In a patient with nonsyndromic tooth agenesis (STHAG4; 150400), van den Boogaard et al. (2012) identified compound heterozygosity for 2 mutations in the WNT10A gene: gly95-to-lys (G95K) and F228I (606268.0003).
In 4 unrelated Thai patients with agenesis of the maxillary permanent canines (STHAG4; 150400), Kantaputra et al. (2014) identified a heterozygous A-to-G transition in the WNT10A gene, resulting in a gly213-to-ser (G213S; rs147680216) substitution. The mother of one of the patients carried the mutation and had peg-shaped maxillary lateral incisors. One of 100 Thai controls also carried the mutation.
In 2 Indian sibs with odontoonychodermal dysplasia (OODD; 257980), Xu et al. (2017) identified homozygosity for a splice site mutation (c.756+1G-A) in intron 3 of the WNT10A gene. The parents were heterozygous for the mutation. qPCR in hair samples from one of the sibs showed the presence of normally spliced exon 1 and exon 2 transcripts but a significant decrease in transcripts resulting from splicing of intron 3. The predicted protein product is truncated after amino acid 252, resulting in absence of part of the conserved C terminus necessary for disulfide bridge formation, Wnt protein secondary structure, and binding to Frizzled receptors (see 603408). The sibs had conical primary teeth, failure to develop permanent teeth, alopecia, and palmoplantar scaling.
In a 14-year-old girl (patient 20-32), born of consanguineous parents, with a clinical diagnosis of odontoonychodermal dysplasia (OODD; 257980), Yu et al. (2019) identified homozygosity for a c.742C-T transition in the WNT10A gene, resulting in an arg248-to-ter (R248X) substitution. The mutation, which was identified by Sanger sequencing, was present in heterozygous state in the parents and a healthy sib. It was not present in 200 healthy controls. The patient had dry skin, hypohidrosis, dystrophic nails, widely spaced primary dentition with absence of 5 deciduous teeth, and complete absence of permanent teeth.
In a 9-year-old girl (patient 14-43) with a clinical diagnosis of odontoonychodermal dysplasia (OODD; 257980), Yu et al. (2019) identified compound heterozygous mutations in the WNT10A gene: a c.826T-A transversion (c.826T-A, NM_025216.2), resulting in a cys276-to-ser (C276S) substitution, and a 1-bp deletion (c.949delG; 606268.0015), resulting in a frameshift and a premature termination codon (Ala317HisfsTer121). The mutations were identified by Sanger sequencing. The parents were each heterozygous for one of the mutations. Neither mutation was present in 200 healthy controls. The patient had absence of permanent dentition, sparse body hair, palmoplantar keratodermas, and hypohidrosis.
For discussion of the 1-bp deletion (c.949delG, NM_025216.2) in the WNT10A gene that was identified in compound heterozygous state in a patient with odontoonychodermal dysplasia (OODD; 257980) by Yu et al. (2019), see 606260.0012.
Adaimy, L., Chouery, E., Megarbane, H., Mroueh, S., Delague, V., Nicolas, E., Belguith, H., de Mazancourt, P., Megarbane, A. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am. J. Hum. Genet. 81: 821-828, 2007. [PubMed: 17847007] [Full Text: https://doi.org/10.1086/520064]
Arzoo, P. S., Klar, J., Bergendal, B., Norderyd, J., Dahl, N. WNT10A mutations account for 1/4 of population-based isolated oligodontia and show phenotypic correlations. Am. J. Med. Genet. 164A: 353-359, 2014. [PubMed: 24449199] [Full Text: https://doi.org/10.1002/ajmg.a.36243]
Bohring, A., Stamm, T., Spaich, C., Haase, C., Spree, K., Hehr, U., Hoffmann, M., Ledig, S., Sel, S., Wieacker, P., Ropke, A. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am. J. Hum. Genet. 85: 97-105, 2009. [PubMed: 19559398] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.001]
Kantaputra, P., Kaewgahya, M., Kantaputra, W. WNT10A mutations also associated with agenesis of the maxillary permanent canines, a separate entity. Am. J. Med. Genet. 164A: 360-363, 2014. [PubMed: 24311251] [Full Text: https://doi.org/10.1002/ajmg.a.36280]
Kantaputra, P., Sripathomsawat, W. WNT10A and isolated hypodontia. Am. J. Med. Genet. 155A: 1119-1122, 2011. [PubMed: 21484994] [Full Text: https://doi.org/10.1002/ajmg.a.33840]
Kirikoshi, H., Sekihara, H., Katoh, M. WNT10A and WNT6, clustered in human chromosome 2q35 region with head-to-tail manner, are strongly coexpressed in SW480 cells. Biochem. Biophys. Res. Commun. 283: 798-805, 2001. [PubMed: 11350055] [Full Text: https://doi.org/10.1006/bbrc.2001.4855]
Plaisancie, J., Bailleul-Forestier, I., Gaston, V., Vaysse, F., Lacombe, D., Holder-Espinasse, M., Abramowicz, M., Coubes, C., Plessis, G., Faivre, L., Demeer, B., Vincent-Delorme, C., and 10 others. Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia. Am. J. Med. Genet. 161A: 671-678, 2013. [PubMed: 23401279] [Full Text: https://doi.org/10.1002/ajmg.a.35747]
van den Boogaard, M.-J., Creton, M., Bronkhorst, Y., van der Hout, A., Hennekam, E., Lindhout, D., Cune, M., Ploos van Amstel, H. K. Mutations in WNT10A are present in more than half of isolated hypodontia cases. J. Med. Genet. 49: 327-331, 2012. [PubMed: 22581971] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100750]
Xu, M., Horrell, J., Snitow, M., Cui, J., Gochnauer, H., Syrett, C. M., Kallish, S., Seykora, J. T., Liu, F., Gaillard, D., Katz, J. P., Kaestner, K. H., and 13 others. WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nature Commun. 8: 15397, 2017. Note: Electronic Article. [PubMed: 28589954] [Full Text: https://doi.org/10.1038/ncomms15397]
Yang, J., Wang, S.-K., Choi, M., Reid, B. M., Hu, Y., Lee, T.-L., Herzog, C. R., Kim-Berman, H., Lee, M., Benke, P. J., Llyod, K. C. K., Simmer, J. P., Hu, J. C.-C. Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds. Molec. Genet. Genomic Med. 3: 40-58, 2015. [PubMed: 25629078] [Full Text: https://doi.org/10.1002/mgg3.111]
Yu, M., Liu, Y., Liu, H., Wong, S.-W., He, H., Zhang, X., Wang, Y., Han, D., Feng, H. Distinct impacts of bi-allelic WNT10A mutations on the permanent and primary dentitions in odonto-onycho-dermal dysplasia. Am. J. Med. Genet. 179A: 57-64, 2019. [PubMed: 30569517] [Full Text: https://doi.org/10.1002/ajmg.a.60682]