CACNA1S mutation-associated dental anomalies: A calcium channelopathy
Issued Date
2023-01-01
Resource Type
ISSN
1354523X
eISSN
16010825
Scopus ID
2-s2.0-85150639001
Pubmed ID
36825457
Journal Title
Oral Diseases
Rights Holder(s)
SCOPUS
Bibliographic Citation
Oral Diseases (2023)
Suggested Citation
Kantaputra P., Butali A., Eliason S., Chalkley C., Nakornchai S., Bongkochwilawan C., Kawasaki K., Kumchiang A., Ngamphiw C., Tongsima S., Ketudat Cairns J.R., Olsen B., Intachai W., Ohazama A., Tucker A.S., Amendt B.A. CACNA1S mutation-associated dental anomalies: A calcium channelopathy. Oral Diseases (2023). doi:10.1111/odi.14551 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81823
Title
CACNA1S mutation-associated dental anomalies: A calcium channelopathy
Author's Affiliation
Laboratory of Biochemistry
Niigata University, Graduate School of Medical and Dental Science
Mahidol University, Faculty of Dentistry
Suranaree University of Technology
University of Iowa
King's College London
University of Iowa Carver College of Medicine
Harvard School of Dental Medicine
University of Iowa College of Dentistry
Thailand National Science and Technology Development Agency
Chiang Mai University
Na-Chauk Hospital
Niigata University, Graduate School of Medical and Dental Science
Mahidol University, Faculty of Dentistry
Suranaree University of Technology
University of Iowa
King's College London
University of Iowa Carver College of Medicine
Harvard School of Dental Medicine
University of Iowa College of Dentistry
Thailand National Science and Technology Development Agency
Chiang Mai University
Na-Chauk Hospital
Other Contributor(s)
Abstract
Objectives: To identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions. Materials and Methods: Clinical and radiographic examinations were performed for eight patients. Whole exome sequencing, mutant protein modelling, qPCR, western blot analysis, scratch assays, immunofluorescence, confocal analysis, in situ hybridization, and scanning electron micrography of teeth were done. Results: All patients had molars with multiple supernumerary cusps, single-cusped premolars, and a reduction in root number. Mutation analysis highlighted a heterozygous c.865A>G; p.Ile289Val mutation in CACNA1S in the patients. CACNA1S is a component of the slowly inactivating L-type voltage-dependent calcium channel. Mutant protein modeling suggested that the mutation might allow leakage of Ca2+ or other cations, or a tightening, to restrict calcium flow. Immunohistochemistry analysis showed expression of Cacna1s in the developing murine tooth epithelium during stages of crown and root morphogenesis. In cell culture, the mutation resulted in abnormal cell migration of transfected CHO cells compared to wildtype CACNA1S, with changes to the cytoskeleton and markers of focal adhesion. Conclusions: The malformations observed in our patients suggest a role for calcium signaling in organization of both cusps and roots, affecting cell dynamics within the dental epithelium.