CACNB3 defects are associated with infantile idiopathic nystagmus

TL;DR

A new gene linked to infantile nystagmus is identified, showing how calcium signaling defects may cause this eye movement disorder.

Contribution

CACNB3 is newly associated with idiopathic infantile nystagmus, revealing a role for calcium signaling in its cause.

Findings

A CACNB3 mutation (c.316G>C) co-segregates with idiopathic infantile nystagmus.

The mutation impairs plasma membrane calcium channel function and increases endoplasmic reticulum calcium release.

Reduced plasma membrane localization of calcium channels is observed in co-localization studies.

Abstract

Infantile nystagmus (IN) is a common neuro-ophthalmological disorder that presents as early-onset involuntary oscillations of the eyes. Here, we report a novel genotype-phenotype correlation that associates sequence alterations in the calcium voltage-gated channel auxiliary subunit beta 3 (CACNB3) gene, encoding the CaVβ3 protein, with idiopathic infantile nystagmus (IIN). Linkage analysis, whole exome and Sanger sequencing identified a homozygous missense mutation (c.316G>C) in CACNB3 co-segregating with IIN. Our calcium imaging experiments suggest that the p.Gly106Arg mutation in the Src homology 3 domain of CaVβ3 may impair voltage-gated calcium channel function at the plasma membrane and may increase ligand-triggered inositol trisphosphate receptor mediated calcium release at the endoplasmic reticulum. Co-localization studies indicate reduced plasma membrane localization of the calcium channel. We propose CACNB3 to be a novel gene associated with IIN. Our findings point towards an important role of calcium-signalling in IIN and may contribute to deciphering its aetiology.

Jüschke et al. report a novel genotype-phenotype correlation between a CACNB3 (CaVβ3) mutation and idiopathic infantile nystagmus. The mutation impairs voltage-gated calcium channel function at the plasma membrane and increases calcium release from the endoplasmic reticulum. This discovery highlights the role of calcium signalling in the aetiology of nystagmus.

Graphical Abstract

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