Abstract
Ectodermal dysplasia is a highly heterogeneous group of disorders that variably affect the derivatives of the ectoderm, primarily skin, hair, nails and teeth. TP63, itself mutated in ectodermal dysplasia, links many other ectodermal dysplasia disease genes through a regulatory network that maintains the balance between proliferation and differentiation of the epidermis and other ectodermal derivatives. The ectodermal knockout phenotype of five mouse genes that regulate and/or are regulated by TP63 (Irf6, Ikkα, Ripk4, Stratifin, and Kdf1) is strikingly similar and involves abnormal balance towards proliferation at the expense of differentiation, but only the first three have corresponding ectodermal phenotypes in humans. We describe a multigenerational Saudi family with an autosomal dominant form of hypohidrotic ectodermal dysplasia in which positional mapping and exome sequencing identified a novel variant in KDF1 that fully segregates with the phenotype. The recapitulation of the phenotype we observe in this family by the Kdf1−/− mouse suggests a causal role played by the KDF1 variant.
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Acknowledgements
We thank the study family for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSHRC for their technical help. This work was supported by KACST Grant 13-BIO1113-20 (FSA) and King Abdullah University of Science and Technology (KAUST) (STA).
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H. E. Shamseldin and O. Khalifa contributed equally.
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439_2016_1741_MOESM1_ESM.pdf
Supplementary material 1 (PDF 429 kb) Figure S1. (A) Prediction of secondary structure (top) and disorder (bottom) for KDF1. F251 is identified by an asterisk. The grey underlined fragment was subjected to ab initio 3D structure prediction, resulting in the model shown in (B), where F521 is highlighted in green, and S218 is shown in yellow. The Quark TM score for the 3D model was 0.56 ± 0.08, and TM score of top 10 best models was 0.63 ± 0.07, indicating that the modeling procedure converged on highly similar models, and hence that the overall fold of the resulting model is close to reality
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Shamseldin, H.E., Khalifa, O., Binamer, Y.M. et al. KDF1, encoding keratinocyte differentiation factor 1, is mutated in a multigenerational family with ectodermal dysplasia. Hum Genet 136, 99–105 (2017). https://doi.org/10.1007/s00439-016-1741-z
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DOI: https://doi.org/10.1007/s00439-016-1741-z