Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations

Abstract

Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a rare disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca2+ homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1, CAPN3 functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca2+ homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.

Circulating miR-206 as a Biomarker for Patients Affected by Severe Limb Girdle Muscle Dystrophies

“…We also describe a group of people affected by calpainopathy (LGMD-R1), the most frequent form of girdle dystrophy, which in European countries would represent about 40–50% of total cases of LGMD [ 15 , 16 , 17 , 18 , 19 ], a recessive form, due to mutations in the gene coding for calpain-3 ( CAPN3 ), a muscle specific family’s member of Ca ++ activated neutral protease [ 20 ]. The identification of the disease locus in chromosome 15 [ 21 ], the first mutations in the CAPN3 gene were then identified both in France [ 22 ] and clinically described in a group of LGMD-R1 patients who lived in a small community [ 23 ].…”

Compound heterozygous CAPN3 variants identified in a family with limb-girdle muscular dystrophy recessive 1

“…The CAPN3 missense variant p.(Asp707Gly) reportedly causes autosomal recessive inheritance, leading to severe and progressive clinical features and typical and evident muscular weakness and atrophies (11,36,37,39). Missense CAPN3 variants not only affect calpain 3 enzymatic activity, but also affect binding between protein molecules, thereby affecting protein integrity (20). Notably, previous studies showed that CAPN3 variants can also cause the autosomal dominant pattern of LGMDD4 and deletion variants c.643_663del21, c.598_612del15, as well as missense variant c.1333G>A (8,40,41) can trigger similarly mild clinical features in the case of LGMDR1.…”

“…It is well-known that missense variants in CAPN3 are the most common type and frequently occur in the cysteine protease and PEF domain of calpain 3. The PEF domain binds four Ca 2+ ions per protomer through EF1, EF2, EF3 and EF5 and three Ca 2+ -binding EF-hands are concentrated near the protease core, which may facilitate calpain 3 homodimerization and calcium ion binding and radically alter the local charge within the dimer during Ca 2+ signaling (20,32). The two CAPN3 variants identified in the present study are respectively located in EF2 and EF3 of the PEF domain and may significantly change the 3D structure and disrupt the conformational stability of domain IV, thereby affecting the transmission of calcium signals.…”

“…CAPN3, localized on chromosome 15q15.1 (16)(17)(18), spans more than 138 kb of genomic DNA with 24 exons and encodes a 94-kDa protease enzyme, calpain 3, consisting of 821 amino acids (NM_000070.2) (19). Calpain 3 protein, a calcium-dependent non-lysosomal neutral cysteine protease widely found in the sarcomere structure, serves a role in muscle regeneration, sarcolemmal repair, muscle assembly and remodeling, as well as cytoskeleton regulation and calcium homeostasis (20,21). The main structure of calpain 3 includes four functional domains, a cysteine protease (II) and penta-EF-hand (PEF) (IV) domains, that respectively code for cysteine protease and calcium-binding domains involved in calcium-dependent enzyme activation (22,23).…”

Current and Future Therapeutic Strategies for Limb Girdle Muscular Dystrophy Type R1: Clinical and Experimental Approaches

“…The full-length form of CAPN3 is expressed mainly in skeletal muscle [8]. CAPN3 demonstrates its non-proteolytic activity by stabilizing Ca 2+ -handling proteins (CSQ [9], SERCA [10], RyR1 [11], CaMKII [11], and NCX3 [12]) and maintaining Ca 2+ homeostasis, which is extremely important and essential for muscle structure and function [5].…”