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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.

Author information

1
Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
2
Department of Forensic Medicine, Hebei Medical University, Hebei, 050017, China.
3
Department of Prosthodontics, School and Hospital of Stomatology of Hebei Medical University, Hebei, 050017, China.
4
Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
5
Human Disease Genomics Center, Peking University, Beijing, 100191, China.
6
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California, 90033, United States of America.

Abstract

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.

PMID:
27144394
PMCID:
PMC4856323
DOI:
10.1371/journal.pone.0154884
[Indexed for MEDLINE]
Free PMC Article

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