A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

Hum Mutat. 2020 Sep;41(9):1507-1513. doi: 10.1002/humu.24066. Epub 2020 Jul 11.


Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. Affected family members had at least three of the following; muscle pain, a LGMD2A pattern of muscle weakness and wasting, muscle fat replacement on magnetic resonance imaging, myopathic muscle biopsy, and elevated creatine kinase. Total calpain 3 protein expression was 4 ± 3% of normal. In vitro analysis of c.1715G>C and the previously described c.643_663del variant indicated that the mutant proteins lack autolytic and proteolytic activity and decrease the quantity of wild-type CAPN3 protein. Our findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3, and that dominantly inherited calpainopathy should be considered for other single variations in CAPN3.

Keywords: calpain 3; calpainopathy; dominant inheritance; limb girdle muscular dystrophy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Calpain / genetics*
  • Child
  • Humans
  • Male
  • Middle Aged
  • Muscle Proteins / genetics*
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Pedigree
  • Young Adult


  • Muscle Proteins
  • CAPN3 protein, human
  • Calpain

Supplementary concepts

  • Limb-girdle muscular dystrophy type 2A