title: Functional Study of Ectodysplasin-A Mutations Causing Non-Syndromic Tooth Agenesis.
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.
authors.affiliation: 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.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
authors.forename: Haochen
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.|Human Disease Genomics Center, Peking University, Beijing, 100191, China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Forensic Medicine, Hebei Medical University, Hebei, 050017, China.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California, 90033, United States of America.
authors.forename: Malcolm L
authors.initials: ML
authors.lastname: Snead
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
authors.forename: Hailan
authors.initials: H
authors.lastname: Feng
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D002460:Cell Line; D053331:Ectodysplasins / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D009805:Odontogenesis / Q000235:genetics*; D014070:Tooth / Q000254:growth & development*; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D055415:Bone Morphogenetic Protein 4; D053331:Ectodysplasins; D016328:NF-kappa B; D051153:Wnt Proteins