HGNC Approved Gene Symbol: APCDD1
Cytogenetic location: 18p11.22 Genomic coordinates (GRCh38): 18:10,454,635-10,489,949 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p11.22 | Hypotrichosis 1 | 605389 | Autosomal dominant | 3 |
The APCDD1 gene encodes a membrane-bound glycoprotein that inhibits Wnt signaling (Shimomura et al., 2010).
By cDNA microarray analysis, Takahashi et al. (2002) identified APCDD1 as a gene downregulated by APC (611731) in the beta-catenin (116806)-T-cell factor (see TCF4; 602228) signaling pathway in SW480 colon cancer cells. They obtained the full-length cDNA by 5-prime RACE. The deduced 514-amino acid protein has a calculated molecular mass of about 59 kD. Northern blot analysis detected a 2.6-kb transcript expressed ubiquitously, with abundant expression in heart, pancreas, prostate, and ovary.
Using luciferase reporter assays and electrophoretic mobility shift assays with the promoter region of APCDD1, Takahashi et al. (2002) determined that beta-catenin and TCF4 directly interact with and induce transcription of APCDD1. Assays performed with functional mutations in each of the TCF4-binding sites indicated that both are required for maximum APCDD1 transcription. Transfection of APCDD1 into LoVo colon cancer cells increased their rate of growth. LoVo-APCDD1 cells transplanted into nude mice showed a tendency toward larger and faster tumor growth than LoVo-vector, but the difference was not statistically significant. Semiquantitative RT-PCR detected increased expression of APCDD1 in 18 of the 27 (67%) tumors examined.
Shimomura et al. (2010) showed that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A (606359) and LRP5 (603506), 2 essential components of Wnt signaling. Functional studies showed that APCDD1 inhibits Wnt signaling in a cell-autonomous manner and functions upstream of beta-catenin (116806). Moreover, APCDD1 repressed activation of Wnt reporters and target genes, and inhibited the biologic effects of Wnt signaling during both the generation of neurons from progenitors in the developing chick nervous system and axis specification in Xenopus laevis embryos.
Takahashi et al. (2002) determined that the APCDD1 gene contains 5 exons and spans about 40 kb. The 5-prime flanking region has 2 potential TCF4-binding sites, and luciferase reporter assays indicated that both are utilized.
By genomic sequence analysis, Takahashi et al. (2002) mapped the APCDD1 gene to chromosome 18p11.
In 3 families with autosomal dominant hypotrichosis simplex (605389), Shimomura et al. (2010) identified a heterozygous missense mutation (L9R; 607479.0001) as the basis of the disorder. The mutation is located in the signal peptide of APCDD1 and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. Shimomura et al. (2010) predicted from functional studies that L9R-mutated APCDD1 functions in a dominant-negative manner to inhibit the stability and membrane localization of the wildtype protein.
In 2 Pakistani and 1 Italian family with autosomal dominant hypotrichosis simplex (HYPT1; 605389), Shimomura et al. (2010) identified a heterozygous T-to-G transversion at nucleotide 26 of the APCDD1 gene (26T-G) that resulted in a leu9-to-arg (L9R) substitution in the signal peptide. The mutation segregated with the phenotype in all families and was absent from 200 unrelated unaffected controls and from SNP databases. The Italian family had been reported by Baumer et al. (2000).
In affected members of a large 5-generation Chinese family segregating hypotrichosis simplex, Li et al. (2012) identified heterozygosity for the L9R mutation, which occurs at a highly conserved residue within the cleavage site of the APCDD1 protein. The mutation was not detected in 100 unrelated Chinese controls. No mutations in the RPL21 (603636) or CDSN (602593) genes were found in any member of this family.
Baumer, A., Belli, S., Trueb, R. M., Schinzel, A. An autosomal dominant form of hereditary hypotrichosis simplex maps to 18p11.32-p11.23 in an Italian family. Europ. J. Hum. Genet. 8: 443-448, 2000. [PubMed: 10878665] [Full Text: https://doi.org/10.1038/sj.ejhg.5200506]
Li, M., Cheng, R., Zhuang, Y., Yao, Z. A recurrent mutation in the APCDD1 gene responsible for hereditary hypotrichosis simplex in a large Chinese family. (Letter) Brit. J. Derm. 167: 952-954, 2012. [PubMed: 22512811] [Full Text: https://doi.org/10.1111/j.1365-2133.2012.11001.x]
Shimomura, Y., Agalliu, D., Vonica, A., Luria, V., Wajid, M., Baumer, A., Belli, S., Petukhova, L., Schinzel, A., Brivanlou, A. H., Barres, B. A., Christiano, A. M. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464: 1043-1047, 2010. [PubMed: 20393562] [Full Text: https://doi.org/10.1038/nature08875]
Takahashi, M., Fujita, M., Furukawa, Y., Hamamoto, R., Shimokawa, T., Miwa, N., Ogawa, M., Nakamura, Y. Isolation of a novel human gene, APCDD1, as a direct target of the beta-catenin/T-cell factor 4 complex with probable involvement in colorectal carcinogenesis. Cancer Res. 62: 5651-5656, 2002. [PubMed: 12384519]