Abstract
Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN.
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Acknowledgements
We are grateful to the affected individuals and their families for their cooperation, and we thank M. Schad (Deutsches Ressourcenzentrum für Genomforschung, Berlin) for help with inverted graphical presentation of CGH data. This research was supported by BMBF (Netzwerk für Ichthyosen und verwandte Verhornungsstörungen (NIRK)), the European Union (Coordination Action GeneSkin) and Forschungspool des Fachbereichs Medizin der Philipps-Universität Marburg.
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This study was designed by K.-H.G. and R.H. Clinical phenotype assessment and proband recruitment were performed by A.K, M.d.C.B., H.E., U.G., M.H., K.H., V.O., M.P., C.S., Z.S., G.T., H.T. and R.H.; genetic mapping, mutation analyses and X inactivation analysis were performed by D.B., B.F. and F.O.; data analysis was performed by K.-H.G., D.B and F.O. and K.-H.G., F.O., A.K. and R.H. contributed to the writing of the paper.
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Supplementary information
Supplementary Fig. 1
Developmental defects associated with FDH. (PDF 668 kb)
Supplementary Fig. 2
MAPH analysis of PORCN in FDH patients GG1, GG2 and GG11. (PDF 651 kb)
Supplementary Fig. 3
Genomic sequences of FDH patients GG3–GG10, encompassing mutations in the PORCN gene, and corresponding wild-type sequences. (PDF 979 kb)
Supplementary Table 1
Two-point linkage analysis for FDH and 15 X-chromosomal markers in family Tu1. (PDF 95 kb)
Supplementary Table 2
Primer pairs and conditions used in PORCN analysis. (PDF 83 kb)
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Grzeschik, KH., Bornholdt, D., Oeffner, F. et al. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet 39, 833–835 (2007). https://doi.org/10.1038/ng2052
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DOI: https://doi.org/10.1038/ng2052
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