Hyperinsulinemic Hypoglycemia Associated with a Ca_V1.2 Variant with Mixed Gain- and Loss-of-Function Effects

Area of Science:

• Genetics
• Cardiology
• Endocrinology

Background:

• The CaV1.2 calcium channel (encoded by CACNA1C) is vital for cardiac function and insulin secretion.
• Gain-of-function CACNA1C mutations cause Timothy syndrome, linked to autism and long QT syndrome, and often hypoglycemia.
• The origin of hypoglycemia in Timothy syndrome patients remains unclear.

Purpose of the Study:

• To investigate a novel CACNA1C mutation identified in a patient with congenital hyperinsulinism (CHI) and hypoglycemia.
• To characterize the electrophysiological effects of this mutation on the CaV1.2 channel.
• To determine the potential link between CACNA1C variants and non-syndromic hyperinsulinemic hypoglycemia.

Main Methods:

• Next-generation sequencing to identify CACNA1C mutations.
• Voltage-clamp recordings to assess channel electrophysiology.
• In silico action potential modeling to simulate cellular effects.

Main Results:

• A novel heterozygous CACNA1C mutation (CaV1.2L566P) was identified in a patient with CHI.
• The CaV1.2L566P mutation exhibits a mixed gain- and loss-of-function electrophysiological phenotype.
• In silico modeling suggests tissue-specific effects on beta cells compared to cardiomyocytes.

Conclusions:

• CACNA1C variants can cause non-syndromic hyperinsulinemic hypoglycemia due to specific channel properties.
• Hypoglycemia associated with CACNA1C variants requires careful clinical attention.
• CACNA1C variants should be considered in the differential diagnosis of congenital hyperinsulinism.