Key result
CaV1.2L566P CACNA1C mutation in congenital hyperinsulinism causes mixed gain- and loss-of-function electrophysiological effects.
Why the study?
The origin of hypoglycemia in patients with CACNA1C gain-of-function mutations causing Timothy syndrome was unproven, and the association of CACNA1C variants with non-syndromic hyperinsulinemic hypoglycemia was unclear.
Case Report (n=1)
CACNA1C variants can cause non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome due to tissue-specific electrophysiological effects.
May warrant CACNA1C testing in non-syndromic hyperinsulinism; leaves open translation of mixed channel effects to human phenotypes.
The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 α1-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.
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Kummer et al. (2022) conducted a case report in Congenital hyperinsulinism (CHI) (n=1). CACNA1C mutation (CaV1.2L566P) was evaluated on Electrophysiological phenotype. The CaV1.2L566P CACNA1C mutation in a patient with congenital hyperinsulinism caused a mixed electrophysiological phenotype of gain- and loss-of-function effects.
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