CACNA1S mutation-associated dental anomalies: A calcium channelopathy

P Kantaputra; A Butali; S Eliason; C Chalkley; S Nakornchai; C Bongkochwilawan; K Kawasaki; A Kumchiang; C Ngamphiw; S Tongsima; J R Ketudat Cairns; B Olsen; W Intachai; A Ohazama; A S Tucker; B A Amendt

doi:10.1111/odi.14551

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CACNA1S mutation-associated dental anomalies: A calcium channelopathy

Journal article

Open access

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CACNA1S mutation-associated dental anomalies: A calcium channelopathy

P Kantaputra, A Butali, S Eliason, C Chalkley, S Nakornchai, C Bongkochwilawan, K Kawasaki, A Kumchiang, C Ngamphiw, S Tongsima, …

Oral diseases, Vol.30(3), pp.1350-1359

02/24/2023

DOI: 10.1111/odi.14551

PMCID: PMC11229413

PMID: 36825457

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11229413/pdf/nihms-2006805.pdfView

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Abstract

To identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions. Clinical and radiographic examinations were performed on eight patients. Whole exome sequencing, mutant protein modelling, qPCR, Western blot analysis, Scratch assays, immunofluorescence, confocal analysis, in situ hybridization, scanning electron micrography of teeth were performed. 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 Ca 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. 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.

Tooth development

Root malformation

Single-rooted molar; Hypodontia

Supernumerary cusps

Calcium homeostasis

Details

Title: Subtitle: CACNA1S mutation-associated dental anomalies: A calcium channelopathy
Creators: P Kantaputra - Chiang Mai University
A Butali - University of Iowa, Iowa Institute for Oral Health Research
S Eliason - Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
C Chalkley - Department of Anatomy and Cell Biology and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA
S Nakornchai - Mahidol University
C Bongkochwilawan - Chiang Mai University
K Kawasaki - Niigata University
A Kumchiang - Na-Chauk Hospital, Na-Chauk, Maha Sarakham, Thailand
C Ngamphiw - National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani, Thailand
S Tongsima - National Biobank of Thailand, National Science and Technology Development Agency (NSTDA), Thailand Science Park, Pathum Thani, Thailand
J R Ketudat Cairns - Chulabhorn Research Institute
B Olsen - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
W Intachai - Chiang Mai University
A Ohazama - Niigata University
A S Tucker - King's College London
B A Amendt
Resource Type: Journal article
Publication Details: Oral diseases, Vol.30(3), pp.1350-1359
DOI: 10.1111/odi.14551
PMID: 36825457
PMCID: PMC11229413
NLM abbreviation: Oral Dis
ISSN: 1354-523X
eISSN: 1601-0825
Grant note: DOI: 10.13039/501100010724, name: Health Systems Research Institute
Language: English
Electronic publication date: 02/24/2023
Academic Unit: Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984368430502771

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