Fam83h null mice support a neomorphic mechanism for human ADHCAI


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: 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

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


Zdroje

1. Chan, H. C., N. M. Estrella, R. N. Milkovich, J. W. Kim, J. P. Simmer, and J. C. Hu. 2011. Target gene analyses of 39 amelogenesis imperfecta kindreds. Eur. J. Oral Sci. 119 (Suppl. 1):311–323.

2. Choi, M., U. I. Scholl, W. Ji, T. Liu, I. R. Tikhonova, P. Zumbo, et al. 2009. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 106:19096–19101.

3. Ding, Y., M. R. Estrella, Y. Y. Hu, H. L. Chan, H. D. Zhang, J. W. Kim, et al. 2009. Fam83h is associated with intracellular vesicles and ADHCAI. J. Dent. Res. 88:991–996.

4. Dunham, W. H., M. Mullin, and A. C. Gingras. 2012. Affinity- purification coupled to mass spectrometry: basic principles and strategies. Proteomics 12:1576–1590.

5. El-Sayed, W., R. C. Shore, D. A. Parry, C. F. Inglehearn, and A. J. Mighell. 2010. Ultrastructural analyses of deciduous teeth affected by hypocalcified amelogenesis imperfecta from a family with a novel Y458X FAM83H nonsense mutation. Cells Tissues Organs 191:235–239.

6. Forman, O. P., J. Penderis, C. Hartley, L. J. Hayward, S. L. Ricketts, and C. S. Mellersh. 2012. Parallel mapping and simultaneous sequencing reveals deletions in BCAN and FAM83H. PLoS Genet. 8:e1002462.

7. Gingras, A. C., Gstaiger, M., Raught, B., Aebersold, R.. 2007. Analysis of protein complexes using mass spectrometry. Nat. Rev. Mol. Cell Biol. 8:645–654.

8. Guerler, A. 2013. B G, Zhang Y. Mapping monomeric threading to protein-protein structure prediction. J. Chem. Inf. Model. 53:717–725.

9. Hart, P. S., S. Becerik, D. Cogulu, G. Emingil, D. Ozdemir-Ozenen, S. T. Han, et al. 2009. Novel FAM83H mutations in Turkish families with autosomal dominant hypocalcified amelogenesis imperfecta. Clin. Genet. 75:401–404.

10. Haubek, D., H. Gjorup, L. G. Jensen, I. Juncker, M. Nyegaard, A. D. Borglum, et al. 2011. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five- generation family with a novel FAM83H nonsense mutation. Int. J. Paediatr. Dent. 21:407–412.

11. Hyun, H. K., S. K. Lee, K. E. Lee, H. Y. Kang, E. J. Kim, P. H. Choung, et al. 2009. Identification of a novel FAM83H mutation and microhardness of an affected molar. Int. Endod. J. 42:1039–1043.

12. Kategaya, L. S., A. Hilliard, L. Zhang, J. M. Asara, L. J. Ptacek, and Y. H. Fu. 2012. Casein kinase 1 proteomics reveal prohibitin 2 function in molecular clock. PLoS ONE 7:e31987.

13. Kim, J. W., S. K. Lee, Z. H. Lee, J. C. Park, K. E. Lee, M. H. Lee, et al. 2008. FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am. J. Hum. Genet. 82:489–494.

14. Knippschild, U., A. Gocht, S. Wolff, N. Huber, J. Lohler, and M. Stoter. 2005. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell. Signal. 17:675–689.

15. Kuga, T., H. Kume, N. Kawasaki, M. Sato, J. Adachi, T. Shiromizu, et al. 2013. A novel mechanism of keratin cytoskeleton organization through casein kinase. J. Cell Sci. 126:4721–4731.

16. Kweon, Y. S., K. E. Lee, J. Ko, J. C. Hu, J. P. Simmer, and J. W. Kim. 2013. Effects of Fam83h overexpression on enamel and dentine formation. Arch. Oral Biol. 58:1148–1154.

17. Lee, S. K., Hu, J. C.J. D. Bartlett, K. E. Lee, B. P. Lin, J. P. Simmer., et al. 2008. Mutational spectrum of FAM83H: the C-terminal portion is required for tooth enamel calcification. Hum. Mutat. 29:E95–E99.

18. Lee, S. K., K. E. Lee, T. S. Jeong, Y. H. Hwang, S. Kim, J. C. Hu, et al. 2011. FAM83H mutations cause ADHCAI and alter intracellular protein localization. J. Dent. Res. 90:377–381.

19. Mendoza, G., T. J. Pemberton, K. Lee, R. Scarel-Caminaga, R. Mehrian-Shai, C. Gonzalez-Quevedo, et al. 2007. A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3. Hum. Genet. 120:653–662.

20. Okamura, H., C. Garcia-Rodriguez, H. Martinson, J. Qin, D. M. Virshup, and A. Rao. 2004. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol. Cell. Biol. 24:4184–4195.

21. Popp, M. W., and L. E. Maquat. 2013. Organizing principles of mammalian nonsense-mediated mRNA decay. Annu. Rev. Genet. 47:139–165.

22. Robinson, C., J. Kirkham, and C. A. Nutman. 1988. Relationship between enamel formation and eruption rate in rat mandibular incisors. Cell Tissue Res. 254:655–658.

23. Shyu, A. B., M. F. Wilkinson, and A. van Hoof. 2008. Messenger RNA regulation: to translate or to degrade. EMBO J. 27:471–481.

24. Simmer, J. P., E. C. Lau, C. C. Hu, T. Aoba, M. Lacey, D. Nelson, et al. 1994. Isolation and characterization of a mouse amelogenin expressed in Escherichia coli. Calcif. Tissue Int. 54:312–319.

25. Simmer, J. P., A. S. Richardson, C. E. Smith, Y. Hu, and J. C. Hu. 2011. Expression of kallikrein-related peptidase 4 in dental and non-dental tissues. Eur. J. Oral Sci. 119(Suppl. 1):226–233.

26. Smith, C. E., A. S. Richardson, Y. Hu, J. D. Bartlett, J. C. Hu, and J. P. Simmer. 2011. Effect of kallikrein 4 loss on enamel mineralization: comparison with mice lacking matrix metalloproteinase 20. J. Biol. Chem. 286:18149– 18160.

27. Song, Y. L., C. N. Wang, C. Z. Zhang, K. Yang, and Z. Bian. 2012. Molecular characterization of amelogenesis imperfecta in Chinese patients. Cells Tissues Organs 196:271–279.

28. Stuckey, J. A., and J. E. Dixon. 1999. Crystal structure of a phospholipase D family member. Nat. Struct. Biol. 6:278–284.

29. Wang S-K, Y. H., J. Yang, C. E. Smith, S. M. Nunez, A. S. Richardson, et al. 2015. Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation. Mol. Genet. Genomic. Med. 3:302–319.

30. Wang, S. K., Y. Hu, J. P. Simmer, F. Seymen, N. M. Estrella, S. Pal, et al. 2013. Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing. J. Dent. Res. 92:266–271.

31. Witkop, C. J. Jr, and J. J. Jr Sauk. 1976. Heritable defects of enamel. Pp. 151–226 in R. E. Stewart and G. H. Prescott, eds. Oral Facial Genetics. C.V. Mosby Co., St. Louis.

32. Wright, J. T., S. Frazier-Bowers, D. Simmons, K. Alexander, P. Crawford, S. T. Han, et al. 2009. Phenotypic variation in FAM83H-associated amelogenesis imperfecta. J. Dent. Res. 88:356–360.

33. Wright, J. T., M. Torain, K. Long, K. Seow, P. Crawford, M. J. Aldred, et al. 2011. Amelogenesis imperfecta: genotype- phenotype studies in 71 families. Cells Tissues Organs. 194:279–283.

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