A Recurrent 3'UTR Variant in CAPN3 Highlights the Diagnostic Impact of Non-Coding Variants in Limb-Girdle Muscular Dystrophies.

CAPN3

Recurrent CAPN3 3'UTR variant (c.*534T>C), combined with a second heterozygous CAPN3 variant, creating a binding site for the RBFOX1 protein and reducing calpain-3 expression

This study characterises a novel variant in the 3' untranslated region (3'UTR) of CAPN3, c.*534T>C, in individuals with persistent hyperCKemia, mostly with proximal muscle weakness. Thirteen individuals from 11 unrelated families carry this variant together with a previously identified heterozygous CAPN3 variant, with persistent hyperCKemia commonly accompanied by proximal weakness and myalgia. Western blot showed absent or markedly reduced calpain-3, and muscle RNA-seq showed reduced CAPN3 levels. In silico analyses indicate that the variant creates a binding site for the RNA-binding protein RBFOX1, and a luciferase reporter assay supports a regulatory effect on calpain-3 expression.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A recurrent non-coding variant, found in 11 families, that completes CAPN3-related limb-girdle muscular dystrophy diagnoses left pending with only one coding variant identified. A direct message for interpretation: with a heterozygous CAPN3 variant and a compatible phenotype, examine the 3'UTR, which coding-exon-focused analysis ignores and a genome covers. Pathogenicity rests on reduced calpain-3 on western blot and a still indirect RBFOX1 mechanism; the phase of the two variants is not specified in the abstract.

Analysis by Dr Thibaut Benquey