Divergent features of mitochondrial deficiencies in LGMD2A associated with novel calpain-3 mutations

Abstract

Limb girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. LGMD2A is caused by mutations in the calpain-3 gene (CAPN3) that encodes a Ca2þ-dependent cysteine protease predominantly expressed in the skeletal muscle. Underlying pathological mechanisms have not yet been fully elucidated. Mitochondrial abnormalities have been variably reported in human subjects with LGMD2A and were more systematically evaluated in CAPN3-knocked out mouse models. We have combined histochemical, immunohistochemical, molecular, biochemical, and ultrastructural analyses in our study in order to better outline mitochondrial features in 2 LGMD2A patients with novel CAPN3-associated mutations. Both patients underwent detailed clinical evaluations, followed by muscle biopsies from the quadriceps muscles. The diagnosis of LGMD2A in both patients was first suspected on the basis of a typical clinical localization of the muscle weakness, and confirmed by molecular investigations. Two novel homozygous mutations, c.2242C>G (p.Arg748Gly) and c.291C>A (p.Phe97Leu) were identified: c.2242C>G (p.Arg748Gly) mutation was associated with a significant mitochondrial mass depletion and myofibrillar disruption in the first patient, while c.291C>A (p.Phe97Leu) mutation was accompanied by reactive mitochondrial proliferation with ragged-red fibers in the second patient. Our results delineate CAPN3 mutation-specific patterns of mitochondrial dysfunction and their ultrastructural characteristics in LGMD2A. VC 2018 American Association of Neuropathologists, Inc. All rights reserved.