Fam83h null mice support a neomorphic mechanism for human ADHCAI

Abstract
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 Fam83h expression 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 al...

Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Shih‐Kai Wang, Yuanyuan Hu, Jie Yang, Charles E. Smith, Amelia S Richardson, Yasuo Yamakoshi, Yuan‐Ling Lee, Figen Seymen, Mine Koruyucu, Koray Gencay, Moses Lee, Murim Choi, Jung‐Wook Kim, Jan C‐C. Hu, James P. Simmer Tags: Original Article Source Type: research