Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside

Abstract

Timothy syndrome is a rare disorder caused by CACNA1C gene mutations and characterized by multi-organ system dysfunctions, including ventricular arrhythmias, syndactyly, dysmorphic facial features, intermittent hypoglycemia, immunodeficiency, developmental delay, and autism. Because of the low morbidity and high mortality at a young age, it remains a huge challenge to establish a diagnosis and treatment system to manage Timothy syndrome patients. Here, we aim to provide a detailed review of Timothy syndrome, discuss the mechanisms underlying dysfunctional Cav1.2 due to CACNA1C mutations, and provide some new emerging evidences in treating Timothy syndrome from cell to bedside, promoting the management of this rare disease. Impact statement The knowledge of Timothy syndrome (TS) caused by dysfunctional Cav1.2 channel due to CACNA1C mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of TS develops. In this review, we focus on the TS-related dysfunctional Cav1.2 and the underlying mechanisms. We update TS-related CACNA1C mutations in a precise way over the past 20 years and summarize all reported TS patients based on their clinical presentations and molecular mechanisms, respectively. We hope this review will provide a new comprehensive way to better understand the electrophysiological mechanisms underlying TS from cell to bedside, promoting the management of TS in practice.

Update on the Molecular Genetics of Timothy Syndrome

“…In addition to validating new variants, in vivo models will be useful for further investigation into the mechanism of TS. The various whole animal model studies were recently reviewed by Han et al (46). Careful characterization of cell and animal models of all known TS variants is essential and will aid in any future development of treatments.…”

Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type

“…The most significant region contained 17 CpG sites, overlapping two genes on chromosome 22 ( CHKB and CPT1B ) with a role in pattern formation and development. Other genes with functions in regulation of developmental processes included LIMS3 , which has a role in neural tissue patterning and differentiation [ 41 ]; PRDM9 , which is involved in histone modification and hence, in regulating the epigenetic machinery [ 42 ]; and CACNA1C , which is associated with Timothy syndrome (TS), a rare neurodevelopmental disorder [ 43 ]. While methylation changes in these regions point to the possibility of the associated pathophysiology, further functional and integrative genomics analysis would be necessary to study the possible causation or correlation.…”

Case Report: Expanding the Phenotypic Spectrum of Timothy Syndrome Type 1: A Sporadic Case With a de novo CACNA1C Pathogenic Variant and Segmental Ileal Dilatation

“…The main cause of death in TS is sudden cardiac death (SCD), likely due to fatal arrhythmias. Beta-blocker therapy has not been shown to protect against SCD ( 4 , 5 ). Dufendach et al ( 6 ), found that Nadolol conferred better protection against SCD compared to other beta blockers like propranolol.…”