CACNA1S mutation‐associated dental anomalies: A calcium channelopathy

Abstract

ObjectivesTo identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions.Materials and MethodsClinical 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.ResultsAll 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.ConclusionsThe 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.

Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families

“…This nding is consistent with previous research linking PITX2 mutation to non-syndromic TA and dental anomalies [32,59] can hinder the bud-to-cap morphogenesis process, potentially leading to TA [72,73]. Calcium signaling, regulated by voltage-gated channels (VDCC) [74] and important in tooth development [75], can be disrupted by mutations in calcium channel genes, such as CACNA1S, leading to dental malformations and abnormalities [76]. These ndings indicate that disruptions in focal adhesion may affect tooth morphogenesis and differentiation, which may lead to TA.…”

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation

“…Although dental defects as well as gingival hyperplasia have been reported in few previous CACNA1C case descriptions, these clinical characteristics have been found only in association with Timothy syndrome phenotype [40][41][42]. Ion channels are well known for being involved in tooth formation [43], additionally, defects in gene encoding L-type calcium channels have been associated with abnormal dentition [44,45]. To the best of our knowledge, in the present study we describe for the first time dental and gingival defects associated with a neurological isolated CACNA1C disorder.…”

Identification of novel candidate genes associated with non-syndromic tooth agenesis in Mongolian families

“…Inhibiting focal adhesion kinase (FAK) can hinder the bud-to-cap morphogenesis process, potentially leading to TA [ 72 , 73 ]. Calcium signaling, regulated by voltage-gated channels (VDCC) [ 74 ] and important in tooth development [ 75 ], can be disrupted by mutations in calcium channel genes, such as CACNA1S, leading to dental malformations and abnormalities [ 76 ]. These findings indicate that disruptions in focal adhesion may affect tooth morphogenesis and differentiation, which may lead to TA.…”