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PLoS One. 2016 May 4;11(5):e0154884. doi: 10.1371/journal.pone.0154884. eCollection 2016.

Functional Study of Ectodysplasin-A Mutations Causing Non-Syndromic Tooth Agenesis.

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Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
Department of Forensic Medicine, Hebei Medical University, Hebei, 050017, China.
Department of Prosthodontics, School and Hospital of Stomatology of Hebei Medical University, Hebei, 050017, China.
Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
Human Disease Genomics Center, Peking University, Beijing, 100191, China.
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California, 90033, United States of America.


Recent studies have demonstrated that ectodysplasin-A (EDA) mutations are associated with non-syndromic tooth agenesis. Indeed, we were the first to report three novel EDA mutations (A259E, R289C and R334H) in sporadic non-syndromic tooth agenesis. We studied the mechanism linking EDA mutations and non-syndromic tooth agenesis in human embryonic kidney 293T cells and mouse ameloblast-derived LS8 cells transfected with mutant isoforms of EDA. The receptor binding capability of the mutant EDA1 protein was impaired in comparison to wild-type EDA1. Although the non-syndromic tooth agenesis-causing EDA1 mutants possessed residual binding capability, the transcriptional activation of the receptor's downstream target, nuclear factor κB (NF-κB), was compromised. We also analyzed the changes of selected genes in other signaling pathways, such as WNT and BMP, after EDA mutation. We found that non-syndromic tooth agenesis-causing EDA1 mutant proteins upregulate BMP4 (bone morphogenetic protein 4) mRNA expression and downregulate WNT10A and WNT10B (wingless-type MMTV integration site family member 10A and 10B) mRNA expression. Our results indicated that non-syndromic tooth agenesis causing EDA mutations (A259E, R289C and R334H) were loss-of-function, and suggested that EDA may regulate the expression of WNT10A, WNT10B and BMP4 via NF-κB during tooth development. The results from our study may help to understand the molecular mechanism linking specific EDA mutations with non-syndromic tooth agenesis.

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