Fam83h null mice support a neomorphic mechanism for human ADHCAI

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Truncation mutations in FAM83H (family with sequence similarity 83, member H) cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), but little is known about FAM83H function and the pathogenesis of ADHCAI. We recruited three ADHCAI families and identified two novel (p.Gln457*; p.Lys639*) and one previously documented (p.Q452*) disease-causing FAM83H mutations. We generated and characterized Fam83h-knockout/lacZ-knockin mice. Surprisingly, enamel thickness, density, Knoop hardness, morphology, and prism patterns were similar in Fam83h^+/+, Fam83h^+/−, and Fam83h^−/− mice. The histology of ameloblasts in all stages of development, in both molars and incisors, was virtually identical in all three genotypes and showed no signs of pathology, although the Fam83h^−/− mice usually died after 2 weeks and rarely survived to 7 weeks. LacZ expression in the knockin mice was used to report Fam83hexpression in the epithelial tissues of many organs, notably in skin and hair follicles, which manifested a disease phenotype. Pull-down studies determined that FAM83H dimerizes through its N-terminal phospholipase D-like (PLD-like) domain and identified potential FAM83H interacting proteins. Casein kinase 1 (CK1) interacts with the FAM83H PLD-like domain via an F²⁷⁰-X-X-X-F²⁷⁴-X-X-X-F²⁷⁸ motif. CK1 can phosphorylate FAM83H in vitro, and many phosphorylation sites were identified in the FAM83H C-terminus. Truncation of FAM83H alters its subcellular localization and that of CK1. Our results support the conclusion that FAM83H is not necessary for proper dental enamel formation in mice, but may act as a scaffold protein that localizes CK1. ADHCAI is likely caused by gain-of-function effects mediated by truncated FAM83H, which potentially mislocalizes CK1 as part of its pathological mechanism.

Keywords:
Amelogenesis imperfecta, gain-of-function, hair defects, knockout mouse, skin defects, truncation mutation

Autoři: Shih-Kai Wang ¹; Yuanyuan Hu ¹; Jie Yang ^1,2; Charles E. Smith ³; Amelia S Richardson ¹; Yasuo Yamakoshi ⁴; Yuan-Ling Lee ⁵; Figen Seymen ⁶; Mine Koruyucu ⁶; Koray Gencay ⁶; Moses Lee ⁷; Murim Choi ⁷; Jung-Wook Kim ^8,*; Jan C-C. Hu ¹; James P. Simmer ^1,*
Působiště autorů: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan ¹; Department of Pediatric Dentistry, School and Hospital of Stomatology, Peking University, Haidian District, Beijing, China ²; Facility for Electron Microscopy Research, Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Quebec, Canada ³; Department of Biochemistry and Molecular Biology, School of Dental Medicine, Tsurumi University, Tsurumi-ku, Yokohama, Japan ⁴; Graduate Institute of Clinical Dentistry, National Taiwan University, Taipei, Taiwan ⁵; Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul, Turkey ⁶; Department of Biomedical Sciences, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea ⁷; Department of Pediatric Dentistry & Dental Research Institute, School of Dentistry, Seoul National University, Chongno-gu, Seoul, Korea ⁸
Vyšlo v časopise: Molecular Genetics & Genomic Medicine 2015; Early View(Early View)
Kategorie: Original Research
prolekare.web.journal.doi_sk: https://doi.org/10.1002/mgg3.178

© 2015 University of Pretoria. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Souhrn

Keywords:
Amelogenesis imperfecta, gain-of-function, hair defects, knockout mouse, skin defects, truncation mutation

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