Variants in CAPN3 Causing Autosomal Dominant...

Variants in CAPN3 Causing Autosomal Dominant Limb–Girdle Muscular Dystrophy Combined With Calpain‐3 Deficiency

Abstract

Limb-girdle muscular dystrophy Type 2A/R1 or calpain-3 deficiency is the most common autosomal recessive limb-girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain-3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain-3 gene in mildly to moderately affected patients with limb-girdle muscular dystrophy without biallelic gene variants in CAPN3. Here, we report four cases with creatine kinase levels above 1500 U/L, mild-to-moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the CAPN3 variant c.304C>T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in CAPN3. The third and fourth patients were heterozygous for c.1371C>G; p.(Asn457Lys) and c.1490C>T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near-complete loss of calpain-3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild-to-moderate proximal weakness, increased level of creatine kinase, and near-complete loss of calpain-3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain-3. This information could aid in determining whether a CAPN3 variant of unknown significance is pathological.

Authors

Krag T; Nasho E; Brady L; Verebi C; Leturcq F; Malfatti E; Duno M; Tarnopolsky M; Vissing J

Journal

Human Mutation, Vol. 2025, No. 1,

Publisher

Wiley

Publication Date

January 1, 2025

DOI

10.1155/humu/9301465

ISSN

1059-7794

Associated Experts

Mark Tarnopolsky

Professor, Faculty of Health Sciences

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