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APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex

Abstract

Hereditary hypotrichosis simplex is a rare autosomal dominant form of hair loss characterized by hair follicle miniaturization1,2. Using genetic linkage analysis, we mapped a new locus for the disease to chromosome 18p11.22, and identified a mutation (Leu9Arg) in the adenomatosis polyposis down-regulated 1 (APCDD1) gene in three families. We show that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A and LRP5—two essential components of Wnt signalling. Functional studies show that APCDD1 inhibits Wnt signalling in a cell-autonomous manner and functions upstream of β-catenin. Moreover, APCDD1 represses activation of Wnt reporters and target genes, and inhibits the biological effects of Wnt signalling during both the generation of neurons from progenitors in the developing chick nervous system, and axis specification in Xenopus laevis embryos. The mutation Leu9Arg is located in the signal peptide of APCDD1, and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. APCDD1(L9R) probably functions in a dominant-negative manner to inhibit the stability and membrane localization of the wild-type protein. These findings describe a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth. As APCDD1 is expressed in a broad repertoire of cell types3, our findings indicate that APCDD1 may regulate a diversity of biological processes controlled by Wnt signalling.

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Figure 1: The HHS phenotype maps on chromosome 18p11.2 at a point mutation in the APCDD1 gene.
Figure 2: Wild-type, but not Leu9Arg mutant APCDD1, inhibits canonical Wnt signalling.
Figure 3: Overexpression of wild-type APCDD1, but not the Leu9Arg mutant, inhibits progenitor proliferation and neuronal specification in the chick spinal cord.
Figure 4: APCDD1 inhibits the Wnt pathway in Xenopus embryos.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Data have been deposited at NCBI under accession codes NM_153000 (APCDD1 mRNA) and NP_694545 (APCDD1 protein).

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Acknowledgements

We are grateful to the family members for their participation in this study, and to H. Lam and M. Zhang for technical assistance. We appreciate the collaboration and discussions with R. M. Bernstein, R. M. Trüeb and members of the A.M.C. laboratory. We thank S. Ishii and J. Miyazaki for supplying the pCXN2.1 vector. We thank C. Jahoda, A. Tomlinson, A. Salic, C. Extavour, L. Shapiro, B. Honig, D. Petrey, R. Vallee, G. Di Paolo and G. Karsenty for discussions and comments on the manuscript, and P. Ducy for sharing reagents. This work was supported in part by USPHS NIH grant R01AR44924 from NIH/NIAMS (A.M.C.). Y.S. is supported by a Research Career Development Award from the Dermatology Foundation. The work in B.A.B.’s laboratory (D.A. and B.A.B.) was supported by grants from the Myelin Repair Foundation and the National Multiple Sclerosis Society (grant RG 3936A7/1). The work in A.H.B.’s laboratory (A.V. and A.H.B.) was supported by NIH grants R01 HD032105 (A.H.B.) and R03HD057334 (A.V.).

Author Contributions A.M.C. and B.A.B. are equally contributing senior authors. The study was conceived, designed and supervised by A.M.C.; laboratory work, phenotyping and sample ascertainment were performed by Y.S., D.A., A.V., V.L., M.W. and A.B.; statistical analyses were performed by L.P.; different aspects of clinical genetics, phenotyping and mutation screening assays were made by M.W., Y.S., A.H.B., S.B., A.S. and A.M.C.; and Y.S., D.A., A.V., V.L., A.H.B., B.A.B. and A.M.C. had considerable input in the experimental design and contributed to the preparation and editing of the manuscript.

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Correspondence to Angela M. Christiano.

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Shimomura, Y., Agalliu, D., Vonica, A. et al. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464, 1043–1047 (2010). https://doi.org/10.1038/nature08875

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