Alternative titles; symbols
HGNC Approved Gene Symbol: CAPN3
SNOMEDCT: 1279886003, 370474006, 715341003; ICD10CM: G71.032;
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38): 15:42,359,501-42,412,317 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.1 | Muscular dystrophy, limb-girdle, autosomal dominant 4 | 618129 | Autosomal dominant | 3 |
| Muscular dystrophy, limb-girdle, autosomal recessive 1 | 253600 | Autosomal recessive | 3 |
The CAPN3 gene encodes calpain-3. The calpains, or calcium-activated neutral proteases (EC 3.4.22.17), are nonlysosomal intracellular cysteine proteases. Mammalian calpains are heterodimers composed of a ubiquitous 80-kD large subunit (e.g., CAPN1, 114220 and CAPN2, 114230) and a common small 30-kD subunit (CAPNS1; 114170). CAPN3 is a muscle-specific large subunit (Sorimachi et al., 1989).
Sorimachi et al. (1989) isolated a clone corresponding to a novel member of the CAPN (symbolized CANP by them) large subunit family from human and rat skeletal muscle cDNA libraries. The deduced protein (p94), corresponding to CAPN3, contains 821 amino acid residues, has a molecular mass of 94 kD, and shows significant sequence homology with other large subunits. The protein could be divided into 4 domains (I to IV) as reported for the CANP large subunit family. Domains II and IV are potential cysteine protease and calcium-binding domains, respectively, and have sequences homologous to the corresponding domains of other CANP large subunits. However, domain I of p94 is significantly different from others. In addition, p94 contains 2 unique sequences of 62 and 77 residues in domains II and III, respectively. In contrast to the ubiquitous expression of other large subunits, Northern blot analysis detected a p94 mRNA in skeletal muscle.
Richard et al. (1995) identified the CAPN3 gene by positional cloning of a region on chromosome 15q containing the gene for autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1; 253600). CAPN3 gene was a particularly attractive candidate because of its functional role in muscle. Richard et al. (1995) reported a gene sequence that differed slightly from that reported by Sorimachi et al. (1989).
Blazquez et al. (2008) identified 4 different CAPN3 mRNA transcripts in human white blood cells. Sequence analysis showed that exon 15 was always absent, whereas exons 6 and 16 could be present or not. There was only 1 transcript detected in muscle.
Richard and Beckmann (1996) found that the mouse Capn3 gene encodes an mRNA of a size similar to the human CANP3 mRNA. The mouse gene directs the synthesis of an 821-amino acid protein.
Richard et al. (1995) demonstrated that the CAPN3 gene contains 24 exons and extends over 40 kb.
Ohno et al. (1990) mapped the CAPN3 gene to chromosome 15.
By somatic cell hybridization, Richard and Beckmann (1996) localized the mouse Capn3 gene to either chromosome 2 or chromosome 4. The results did not allow distinction between these 2 chromosomes, since all hybrids carrying mouse chromosome 2 also carried chromosome 4. The fact that isolated murine YACs amplified a sequence tagged site (STS) for the TYRO3 gene (600341), which maps to human chromosome 15, suggested to Richard and Beckmann (1996) that the 2 genes are adjacent in the mouse. Homology between mouse chromosome 2 and human chromosome 15 is well established by a number of examples of synteny; no homology of synteny has been demonstrated between human 15 and mouse 4.
In COS-1 cells, Huang et al. (2008) demonstrated that calpain-3 and AHNAK (103390) colocalize at the I-band near the A-I junction in skeletal muscle, that calpain-3 cleaves AHNAK, and that this cleavage results in decreased levels of AHNAK. Studies of AHNAK fusion protein constructs showed that calpain-3 can cleave AHNAK at 2 sites in the N terminus and 3 sites in the C terminus, but not at the central M region. Cleavage of AHNAK disrupted its binding to dysferlin (DYSF; 603009) and myoferlin (FER1L3; 604603). Skeletal muscle from 4 patients with autosomal recessive LGMD due to CAPN3 mutations (LGMDR1) showed increased levels of AHNAK at the sarcolemma and blood vessels. Huang et al. (2008) concluded that CAPN3 plays a role in the dysferlin protein complex and that disruption of CAPN3 function may affect muscle membrane repair and remodeling.
Sarparanta et al. (2010) found that C-terminal domains of the muscle-specific protein myospryn (CMYA5; 612193) interacted with calpain-3. Myospryn appeared to stabilize full-length calpain-3 against proteolytic autoactivation, and active calpain-3 used myospryn as a substrate.
Autosomal Recessive Limb-Girdle Muscular Dystrophy 1
By a mutation screen in families with autosomal recessive limb-girdle muscular dystrophy-1 (LGMDR1; 253600), earlier designated LGMD2A, Richard et al. (1995) identified biallelic mutations in the CAPN3 gene, including nonsense, splice site, frameshift, and missense mutations (see, e.g., 114240.0001, 114240.0002, and 114240.0003). The mutations segregated with the disorder in the families. Six of the mutations were found within an inbred population on Reunion Island, located in the Indian Ocean, and haplotype analysis suggested the existence of at least 1 more mutation in the group. The occurrence of multiple independent mutations in the isolated population on Reunion Island rather than the finding of an expected founder mutation was referred to as the 'Reunion paradox' by Richard et al. (1995). They suggested that LGMD2A, instead of being a monogenic disorder, might have a more complex inheritance pattern in which expression of calpain mutations is dependent on genetic background, either nuclear or mitochondrial; see INHERITANCE section in 253600.
Richard et al. (1997) studied 21 LGMD pedigrees of various origins: France, Israel, Lebanon, Switzerland, United States, Italy, and Turkey. Nine of the 23 families showed linkage to chromosome 15, whereas such linkage was excluded in 10 and was inconclusive in 4. A search for CAPN3 mutations uncovered 19 novel mutations in addition to the 16 described previously (see, e.g., 114240.0004; 114240.0005). A survey of clinical features showed great variability. All patients showed elevated serum creatine kinase in a range of 7 to 84 times the upper limit of normal, marked intra- and interfamilial phenotypic variability in age of onset (range 2.5 to 40 years), and loss of ambulation. For example, affected individuals in 1 family presented with a very mild phenotype, with onset at ages 30 and 40 years, and were still ambulatory at ages 54 and 66 years, respectively. In contrast, 2 Lebanese sibs had onset at age 6 years and had loss of independent walking at ages 13 years and 15 years.
Fanin et al. (2005) identified mutations in the CAPN3 gene in 70 (33%) of 214 patients with limb-girdle muscular dystrophy in Italy. The prevalence of LGMD2A was estimated at 9.47 per million inhabitants in northeastern Italy. Two founder mutations were identified (500delA, 114240.0009; R490Q, 114240.0010). Todorova et al. (2007) identified mutations in the CAPN3 gene in 20 (42%) of 48 unrelated Bulgarian patients with muscular dystrophy. Three novel and 6 recurrent mutations were identified. Forty percent of the patients were homozygous for the 500delA mutation, and 70% carried it on at least 1 allele.
By high-throughput denaturing HPLC, Piluso et al. (2005) scanned the CAPN3 gene in 530 individuals with different grades of symptoms consistent with LGMD. They found 141 LGMD2A patients carrying 82 different CAPN3 mutations, of which 45 were novel. Females had a more favorable course than males. In 94% of the most severely affected LGMD2A patients, the defect was also discovered in the second allele. CAPN3 mutations were found in 35.1% of patients with classic LGMD phenotypes, 18.4% of atypical patients, and 12.6% of patients with high serum creatine kinase levels. Piluso et al. (2005) broadened the spectrum of LGMD2A phenotypes and set the carrier frequency at 1:103.
Among 46 European patients suspected to have LGMD2A based on Western blot results, Duno et al. (2008) found that 16 patients had mutations in the CAPN3 gene identified by both direct genomic sequencing and cDNA analysis. Both mutant alleles were demonstrated in 10 patients. A total of 16 mutations were identified, including 5 novel mutations. Only 3 of the genetically confirmed LGMD2A patients were of Danish origin, indicating a 5- to 6-fold lower prevalence in Denmark compared to other European countries.
Prior to the identification of CAPN3 as the defective gene in LGMDR1, all identified molecular mechanisms in muscular dystrophies had involved structural components of muscle. CAPN3 appears to have a very rapid turnover mediated by autocatalysis, possibly reflecting the need for precise regulation of its activity. Furthermore, CAPN3 shows a nuclear localization, possibly mediated by the nuclear translocation signal in the IS2 region. Richard et al. (1995) favored the idea that the CAPN3 protein is involved in the control of gene expression by regulating the turnover or activity of transcription factors or of their inhibitors.
Ono et al. (1998) constructed 9 CAPN3 missense point mutations and analyzed the unique properties of the resultant protein product. All mutants completely or almost completely lost proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possessed autolytic activity and/or connectin/titin (TTN; 188840)-binding ability, indicating that these properties are not necessary for the LGMDR1 phenotype. These results provided strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to muscular dystrophies.
Zatz and Starling (2005) reviewed the roles of calpains in disease with specific reference to the etiologic role of mutations in CAPN3 in LGMD2A.
In many patients with LGMDR1, loss-of-function mutations cause enzymatic inactivation of calpain-3 while protein quantity remains normal. Because the diagnosis of calpainopathy is obtained by identifying calpain-3 protein deficiency or mutations in the CAPN3 gene, the identification of such patients is difficult. Fanin et al. (2007) used a functional in vitro assay to test calpain-3 autolytic function in a large series of muscle biopsy specimens from patients with unclassified LGMD/hyperCKemia who had been shown to have normal calpain-3 protein quantity. Of 148 muscle biopsy specimens tested, 17 (11%) had lost normal autolytic function. The CAPN3 gene mutations were identified in 15 of the 17 patients (88%), who accounted for about 20% of the total patients with LGMDR1 diagnosed in their series.
Autosomal Dominant Limb-Girdle Muscular Dystrophy 4
In 36 patients from 10 families of northern European descent with autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4; 618129), earlier designated LGMD1I, Vissing et al. (2016) identified a heterozygous in-frame 21-bp deletion in the CAPN3 gene (c.643_663del21; 114240.0011). Haplotype analysis of 4 families indicated a founder effect. Analysis of several patients' muscle tissue showed normal mRNA levels and no evidence of nonsense-mediated mRNA decay, but significantly decreased CAPN3 protein levels, at less than 15% of control values. Vissing et al. (2016) postulated that the in-frame nature of the mutation may have led to expression of a mutated protein that could have a dominant-negative effect.
In 3 unrelated patients of northern European descent with LGMDD4, Martinez-Thompson et al. (2018) identified the same heterozygous 21-bp deletion in the CAPN3 gene that had been reported by Vissing et al. (2016). The deletion resulted in the deletion of residues Ser215_Gly221 in the first structural domain. Functional studies of the variant were not performed, but Western blot analysis of patient tissues showed greatly decreased amounts of CAPN3 protein.
Tagawa et al. (2000) created transgenic mice that expressed an inactive mutant of p94, in which the active site cys129 is replaced by ser (p94:C129S). Transgenic mice expressing p94:C129S mRNA showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic mice showed increased numbers of lobulated and split fibers, respectively, which are often observed in limb-girdle muscular dystrophy muscles. Centrally placed nuclei were also frequently found in the EDL muscle of the transgenic mice, whereas wildtype mice of the same age had almost none. More p94 protein was produced in aged transgenic mice muscles, and the protein showed significantly less autolytic degradation activity than that in wildtype mice. The authors hypothesized that accumulation of p94:C129S protein caused these myopathy phenotypes.
The giant protein titin (188840) serves a primary role as a scaffold for sarcomere assembly; one potential mediator of this process is calpain-3. To test the hypothesis that calpain-3 mediates remodeling during myofibrillogenesis, Kramerova et al. (2004) generated Capn3-knockout (C3KO) mice. The mice were atrophic, with small foci of muscular necrosis. Myogenic cells fused normally in vitro, but lacked well-organized sarcomeres, as visualized by electron microscopy. Titin distribution was normal in longitudinal sections from the C3KO mice; however, electron microscopy of muscle fibers showed misaligned A-bands. In vitro studies revealed that calpain-3 can bind and cleave titin and that some mutations that are pathogenic in human muscular dystrophy result in reduced affinity of calpain-3 for titin. Kramerova et al. (2004) suggested a role for calpain-3 in myofibrillogenesis and sarcomere remodeling.
Kramerova et al. (2005) showed that the rates of atrophy and growth were decreased in C3KO mouse muscles under conditions promoting sarcomere remodeling. In wildtype mice, ubiquitinated proteins accumulated during muscle reloading, possibly reflecting removal of atrophy-specific and damaged proteins. The increase in ubiquitination correlated with an increase in calpain-3 expression. There was upregulation of heat shock proteins in C3KO muscles following challenge with a physiologic condition that required highly increased protein degradation. Old C3KO mice showed evidence of insoluble protein aggregate formation in skeletal muscles. Kramerova et al. (2005) suggested that accumulation of aged and damaged proteins may lead to cellular toxicity and a cell stress response in C3KO muscles, and that these characteristics may be pathologic features of LGMDR1.
Huebsch et al. (2005) generated CAPN3 overexpressing transgenic (C3Tg) and C3KO mice and showed that overexpression of CAPN3 exacerbated mdm disease, leading to a shorter life span and more severe muscular dystrophy. However, C3KO/mdm double-mutant mice showed no change in the progression or severity of disease, indicating that aberrant CAPN3 activity is not a primary mechanism in this disease. The authors examined the treadmill locomotion of heterozygous +/mdm mice and detected a significant increase in stride time with a concomitant increase in stance time. These altered gait parameters were completely corrected by CAPN3 overexpression in C3Tg/+/mdm mice, suggesting a CAPN3-dependent role for the N2A domain of TTN in the dynamics of muscle contraction.
Kramerova et al. (2009) reported both morphologic and biochemical evidence of mitochondrial abnormalities in C3KO mouse muscles, including irregular ultrastructure and distribution of mitochondria. The morphologic abnormalities in C3KO muscles were associated with reduced in vivo mitochondrial ATP production. Mitochondrial abnormalities in C3KO muscles also correlated with the presence of oxidative stress; increased protein modification by oxygen free radicals and an elevated concentration of the antioxidative enzyme Mn-superoxide dismutase (SOD2; 147460) were observed in C3KO muscles. The activity of the beta-oxidation enzyme, VLCAD (ACADVL; 609575), was decreased in C3KO mitochondrial fractions compared with wildtype, suggestive of a general mitochondrial dysfunction. Kramerova et al. (2009) suggested that mitochondrial abnormalities leading to oxidative stress and energy deficit may be important pathologic features of calpainopathy and possibly represent secondary effects of the absence of calpain-3.
In affected members of 10 Amish families from northern Indiana with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Richard et al. (1995) identified homozygosity for a 2306G-A transition in exon 22 of the CAPN3 gene, resulting in an arg769-to-gln (R769Q) substitution in domain IV of the protein within the third EF-hand of the helix-loop junction. The substitution occurred in a residue conserved throughout all members of the calpain family in all species. This nucleotide change was not present in patients from the 6 southern Indiana Amish LGMD families for which the chromosome 15 locus was excluded by linkage analysis, thus confirming the genetic heterogeneity of this disease in the Amish. The slowly progressive muscle weakness was usually first evident in the pelvic girdle, and then spread to the upper limbs while sparing facial muscles. Unlike the findings in Reunion Islanders, the disorder in the northern Indiana Amish appeared to be fully penetrant, and Richard et al. (1995) suggested a digenic model with a second locus to account for this inheritance pattern.
The same R769Q mutation was found by Richard et al. (1995) in affected members of a Brazilian family; the mutation was within a completely different haplotype from that observed in the Amish families.
Pratt et al. (1997) found no phenotypically normal R769Q homozygotes among 580 DNA samples from Amish individuals in a northern Indiana county. In addition, mitochondrial studies gave no evidence of a modifying mitochondrial gene. These findings argued against possible digenic inheritance postulated by Richard et al. (1995).
In members of a family from Reunion Island who had limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Richard et al. (1995) found homozygosity for 1715G-A transition in exon 13 of the CAPN3 gene, resulting in an arg572-to-gln (R572Q) substitution inside domain III. This residue is highly conserved throughout all known calpains. The mutation, detectable by loss of a MspI restriction site, was present only in this family and in no other examined LGMD2A families or unrelated controls. It was 1 of 6 different CAPN3 mutations found in Reunion Island patients, and at least 1 more mutation was predicted from haplotype analysis.
In a Brazilian family with limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Richard et al. (1995) identified a homozygous 328C-T transition in exon 2 of the CAPN3 gene, resulting in an arg110-to-ter (R110X) substitution. The parents were consanguineous.
In patients with limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Richard et al. (1997) described a ser86-to-phe (S86F) mutation in the CAPN3 gene. Patients who were homozygous for this mutation had disease onset at age 6 to 7 years and presented with severe weakness in their lower limbs, leading to loss of mobility less than 8 years after onset. In contrast, their cousins who were compound heterozygotes for the S86F and P319L (114240.0005) mutations were comparatively mildly affected, with disease onset at age 15 to 17 years on average, and with loss of mobility at age 32 years for 1 of them, whereas the 2 others were still walking at ages 29 years and 28 years. All healthy heterozygotes carrying the S86F mutation had mildly elevated creatine kinase (CK) levels. This observation suggested that the mutation affects muscle cells in a somewhat dominant manner. In this kindred, 2 patients belonging to different branches of the family were diagnosed independently with polymyositis. A muscle biopsy of 1 of them showed minimal abnormalities at the limits of significance. Both patients were treated with steroids for an extended period. Eventually, family history led to a consideration of the diagnosis of muscular dystrophy. Only the identification of the pathogenic mutation allowed the definitive diagnosis of LGMD2A.
For discussion of the pro319-to-leu (P319L) mutation in the CAPN3 gene that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2A (LGMDR1; 253600) by Richard et al. (1997), see 114240.0004.
In Guipuzcoa, a small mountainous Basque province in northern Spain, Urtasun et al. (1998) found the highest prevalence rate of limb-girdle muscular dystrophy described to that time: 69 per million. In 28 families with 38 individuals who had autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), mutations in the CAPN3 gene were identified. The predominant Basque mutation was a frameshift in exon 22 (2362AG-to-TCATCT). This mutation was carried by 2 different haplotypes, which were thought to have been derived from a single ancestral founder haplotype by microsatellite mutation. The common Basque frameshift mutation had previously been identified in 1 Brazilian, 1 French, and 1 American family (Richard et al., 1997). Since their data suggested a founder effect for this frameshift mutation in the Basque population, and because the families with the mutation described by Richard et al. (1997) shared the same haplotype, Urtasun et al. (1998) speculated on a Basque origin for this mutation, which could have moved to Brazil, America, and Reunion by immigration.
Krahn et al. (2006) reported 3 unrelated patients with the CAPN3 Basque mutation who were originally diagnosed with eosinophilic myositis (see 253600) based on skeletal muscle biopsy in the first decade of life. All patients presented initially with increased serum creatine kinase. Skeletal muscle biopsies showed focal inflammatory lesions with eosinophilic infiltration and necrotic muscle fibers with no evidence of parasites. Clinically, the patients had muscle weakness and difficulty walking that increased with age. Krahn et al. (2006) suggested that eosinophilic myositis may be an early and transient feature in calpainopathies, because it was not present in biopsies from older patients with typical LGMD2A.
Kawai et al. (1998) reported on the clinical, pathologic, and genetic features of 7 patients with limb-girdle muscular dystrophy type 2A (LGMDR1; 253600) from 3 consanguineous Japanese families. The mean age of onset was 9.7 years +/- 3.1 years, and loss of ambulation occurred at 38.5 +/- 2.1 years. Muscle atrophy was predominant in the pelvic and shoulder girdles and proximal limb muscles. In 2 families, an identical 1080G-C transversion was found in the CAPN3 gene; a frameshift mutation (1796insA; 114240.0008) was found in the third family. The former mutation resulted in a trp360-to-cys (T360C) substitution in the proteolytic site of calpain-3, and the latter in a deletion of the Ca(2+)-binding domain. (In their article, Kawai et al. (1998) reported the amino acid substitution as trp360-to-cys in Figure 6 and in the text, but as trp360-to-arg in the abstract.)
For discussion of the 1-bp insertion in the CAPN3 gene (1796insA) that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2A (LGMDR1; 253600) by Kawai et al. (1998), see 114240.0007.
In Croatian patients with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Canki-Klain et al. (2004) identified a 1-bp deletion (550delA) in exon 4 of the CAPN3 gene that was the most common mutation, with a prevalence of 76% of mutant CAPN3 alleles. The detection of 4 healthy 550delA heterozygous individuals yielded a frequency of 1 in 133 (0.75%) in the general Croatian population. All 4 carriers originated from an island and mountain region near the Adriatic, indicating a probable founder effect.
Fanin et al. (2005) identified the 550delA mutation in several patients with LGMD from northeastern Italy. The mutation occurred in both the homozygous state and in compound heterozygosity with another CAPN3 mutation. The 550delA mutation accounted for 9 (40%) of 23 mutant CAPN3 alleles from patients specifically from the Friuli region, and haplotype analysis indicated a founder effect. Fanin et al. (2005) concluded that LGMDR1 may be the most frequent autosomal recessive neuromuscular disorder in this region of Italy.
Todorova et al. (2007) identified mutations in the CAPN3 gene in 20 (42%) of 48 unrelated Bulgarian patients with muscular dystrophy. Forty percent of the patients were homozygous for the 500delA mutation, and 70% carried it on at least 1 allele.
In several patients with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600) from 3 unrelated families in northeastern Italy, Fanin et al. (2005) identified a homozygous arg490-to-gln (R490Q) mutation in the CAPN3 gene. Another patient was compound heterozygous for the R490Q mutation and 550delA (114240.0009). The R490Q mutation accounted for 6 (46%) of 13 mutant CAPN3 alleles from patients specifically from the Venezia district, and haplotype analysis indicated a founder effect.
In 36 patients from 10 families of northern European descent with autosomal dominant limb-girdle muscular dystrophy type 1I (LGMDD4; 618129), Vissing et al. (2016) identified a heterozygous in-frame 21-bp deletion (c.643_663del21, NM_000070) in the CAPN3 gene. The variant is present at an allele frequency of 0.006% among individuals of European descent in the ExAC database. Haplotype analysis of 4 families indicated a founder effect. Analysis of several patients' muscle tissue showed normal mRNA levels and no evidence of nonsense-mediated mRNA decay, but significantly decreased CAPN3 protein levels, at less than 15% of control values. Vissing et al. (2016) postulated that the in-frame nature of the mutation may have led to expression of a mutated protein that could have a dominant-negative effect.
In 3 unrelated patients of northern European descent with LGMDD4, Martinez-Thompson et al. (2018) identified the same heterozygous 21-bp deletion in the CAPN3 gene that had been reported by Vissing et al. (2016). The deletion resulted in the deletion of residues Ser215_Gly221 in the first structural domain. The mutations were found by next-generation, whole-exome, or Sanger sequencing; all were confirmed by Sanger sequencing. Each proband had a family history of the disorder, although not all affected family members were available for genetic testing. Functional studies of the variant were not performed, but Western blot analysis of patient tissues showed greatly decreased amounts of the CAPN3 protein.
Blazquez, L., Azpitarte, M., Saenz, A., Goicoechea, M., Otaegui, D., Ferrer, X., Illa, I., Gutierrez-Rivas, E., Vilchez, J. J., Lopez de Munain, A. Characterization of novel CAPN3 isoforms in white blood cells: an alternative approach for limb-girdle muscular dystrophy 2A diagnosis. Neurogenetics 9: 173-182, 2008. [PubMed: 18563459] [Full Text: https://doi.org/10.1007/s10048-008-0129-1]
Canki-Klain, N., Milic, A., Kovac, B., Trlaja, A., Grgicevic, D., Zurak, N., Fardeau, M., Leturcq, F., Kaplan, J.-C., Urtizberea, J. A., Politano, L., Piluso, G., Feingold, J. Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia. Am. J. Med. Genet. 125A: 152-156, 2004. Note: Erratum: Am. J. Med. Genet. 130A: 218 only, 2004. [PubMed: 14981715] [Full Text: https://doi.org/10.1002/ajmg.a.20408]
Duno, M., Sveen, M.-L., Schwartz, M., Vissing, J. cDNA analyses of CAPN3 enhances mutation detection and reveals a low prevalence of LGMD2A patients in Denmark. Europ. J. Hum. Genet. 16: 935-940, 2008. [PubMed: 18337726] [Full Text: https://doi.org/10.1038/ejhg.2008.47]
Fanin, M., Nascimbeni, A. C., Angelini, C. Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations. J. Med. Genet. 44: 38-43, 2007. [PubMed: 16971480] [Full Text: https://doi.org/10.1136/jmg.2006.044859]
Fanin, M., Nascimbeni, A. C., Fulizio, L., Angelini, C. The frequency of limb girdle muscular dystrophy 2A in northeastern Italy. Neuromusc. Disord. 15: 218-224, 2005. [PubMed: 15725583] [Full Text: https://doi.org/10.1016/j.nmd.2004.11.003]
Huang, Y., de Morree, A., van Remoortere, A., Bushby, K., Frants, R. R., Dunnen, J. T., van der Maarel, S. Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum. Molec. Genet. 17: 1855-1866, 2008. [PubMed: 18334579] [Full Text: https://doi.org/10.1093/hmg/ddn081]
Huebsch, K. A., Kudryashova, E., Wooley, C. M., Sher, R. B., Seburn, K. L., Spencer, M. J., Cox, G. A. Mdm muscular dystrophy: interactions with calpain 3 and a novel functional role for titin's N2A domain. Hum. Molec. Genet. 14: 2801-2811, 2005. [PubMed: 16115818] [Full Text: https://doi.org/10.1093/hmg/ddi313]
Kawai, H., Akaike, M., Kunishige, M., Inui, T., Adachi, K., Kimura, C., Kawajiri, M., Nishida, Y., Endo, I., Kashiwagi, S., Nishino, H., Fujiwara, T., Okuno, S., Roudaut, C., Richard, I., Beckmann, J. S., Miyoshi, K., Matsumoto, T. Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families. Muscle Nerve 21: 1493-1501, 1998. [PubMed: 9771675] [Full Text: https://doi.org/10.1002/(sici)1097-4598(199811)21:11<1493::aid-mus19>3.0.co;2-1]
Krahn, M., Lopez de Munain, A., Streichenberger, N., Bernard, R., Pecheux, C., Testard, H., Pena-Segura, J. L., Yoldi, E., Cabello, A., Romero, N. B., Poza, J. J., Bouillot-Eimer, S., Ferrer, X., Goicoechea, M., Garcia-Bragado, F., Leturcq, F., Urtizberea, J. A., Levy, N. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann. Neurol. 59: 905-911, 2006. [PubMed: 16607617] [Full Text: https://doi.org/10.1002/ana.20833]
Kramerova, I., Kudryashova, E., Tidball, J. G., Spencer, M. J. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum. Molec. Genet. 13: 1373-1388, 2004. [PubMed: 15138196] [Full Text: https://doi.org/10.1093/hmg/ddh153]
Kramerova, I., Kudryashova, E., Venkatraman, G., Spencer, M. J. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway. Hum. Molec. Genet. 14: 2125-2134, 2005. Note: Erratum: Hum. Molec. Genet. 16: 1006 only, 2007. [PubMed: 15961411] [Full Text: https://doi.org/10.1093/hmg/ddi217]
Kramerova, I., Kudryashova, E., Wu, B., Germain, S., Vandenborne, K., Romain, N., Haller, R. G., Verity, M. A., Spencer, M. J. Mitochondrial abnormalities, energy deficit and oxidative stress are features of calpain 3 deficiency in skeletal muscle. Hum. Molec. Genet. 18: 3194-3205, 2009. [PubMed: 19483197] [Full Text: https://doi.org/10.1093/hmg/ddp257]
Martinez-Thompson, J. M., Niu, Z., Tracy, J. A., Moore, S. A., Swenson, A., Wieben, E. D., Milone, M. Autosomal dominant calpainopathy due to heterozygous CAPN3 c.643_663del21. Muscle Nerve. 57: 679-683, 2018. [PubMed: 28881388] [Full Text: https://doi.org/10.1002/mus.25970]
Ohno, S., Minoshima, S., Kudoh, J., Fukuyama, R., Ohmi-Imajoh, S., Suzuki, K., Shimizu, Y., Shimizu, N. Four genes for the calpain family locate on four distinct human chromosomes. Cytogenet. Cell Genet. 53: 225-229, 1990. [PubMed: 2209092] [Full Text: https://doi.org/10.1159/000132937]
Ono, Y., Shimada, H., Sorimachi, H., Richard, I., Saido, T. C., Beckmann, J. S., Ishiura, S., Suzuki, K. Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A. J. Biol. Chem. 273: 17073-17078, 1998. [PubMed: 9642272] [Full Text: https://doi.org/10.1074/jbc.273.27.17073]
Piluso, G., Politano, L., Aurino, S., Fanin, M., Ricci, E., Ventriglia, V. M., Belsito, A., Totaro, A., Saccone, V., Topaloglu, H., Nascimbeni, A. C., Fulizio, L., Broccolini, A., Canki-Klain, N., Comi, L. I., Nigro, G., Angelini, C., Nigro, V. Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. J. Med. Genet. 42: 686-693, 2005. [PubMed: 16141003] [Full Text: https://doi.org/10.1136/jmg.2004.028738]
Pratt, V. M., Jackson, C. E., Wallace, D. C., Gurley, D. S., Feit, A., Feldman, G. L. DNA studies of limb-girdle muscular dystrophy type 2A in the Amish exclude a modifying mitochondrial gene and show no evidence for a modifying nuclear gene. (Letter) Am. J. Hum. Genet. 61: 231-233, 1997. [PubMed: 9246005] [Full Text: https://doi.org/10.1016/S0002-9297(07)64296-7]
Richard, I., Beckmann, J. S. Molecular cloning of mouse Canp3, the gene associated with limb-girdle muscular dystrophy 2A in human. Mammalian Genome 7: 377-379, 1996. [PubMed: 8661728] [Full Text: https://doi.org/10.1007/s003359900108]
Richard, I., Brenguier, L., Dincer, P., Roudaut, C., Bady, B., Burgunder, J.-M., Chemaly, R., Garcia, C. A., Halaby, G., Jackson, C. E., Kurnit, D. M., Lefranc, G., Legum, C., Loiselet, J., Merlini, L., Nivelon-Chevallier, A., Ollagnon-Roman, E., Restagno, G., Topaloglu, H., Beckmann, J. S. Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. Am. J. Hum. Genet. 60: 1128-1138, 1997. [PubMed: 9150160]
Richard, I., Broux, O., Allamand, V., Fougerousse, F., Chiannilkulchai, N., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Hillaire, D., Passos-Bueno, M.-R., Zatz, M., Tischfield, J. A., Fardeau, M., Jackson, C. E., Cohen, D., Beckmann, J. S. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81: 27-40, 1995. [PubMed: 7720071] [Full Text: https://doi.org/10.1016/0092-8674(95)90368-2]
Sarparanta, J., Blandin, G., Charton, K., Vihola, A., Marchand, S., Milic, A., Hackman, P., Ehler, E., Richard, I., Udd, B. Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies. J. Biol. Chem. 285: 30304-30315, 2010. [PubMed: 20634290] [Full Text: https://doi.org/10.1074/jbc.M110.108720]
Sorimachi, H., Imajoh-Ohmi, S., Emori, Y., Kawasaki, H., Ohno, S., Minami, Y., Suzuki, K. Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types: specific expression of the mRNA in skeletal muscle. J. Biol. Chem. 264: 20106-20111, 1989. [PubMed: 2555341]
Tagawa, K., Taya, C., Hayashi, Y., Nakagawa, M., Ono, Y., Fukuda, R., Karasuyama, H., Toyama-Sorimachi, N., Katsui, Y., Hata, S., Ishiura, S., Nonaka, I., Seyama, Y., Arahata, K., Yonekawa, H., Sorimachi, H., Suzuki, K. Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A. Hum. Molec. Genet. 9: 1393-1402, 2000. [PubMed: 10814721] [Full Text: https://doi.org/10.1093/hmg/9.9.1393]
Todorova, A., Georgieva, B., Tournev, I., Todorov, T., Bogdanova, N., Mitev, V., Mueller, C. R., Kremensky, I., Horst, J. A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients. Neurogenetics 8: 225-229, 2007. [PubMed: 17318636] [Full Text: https://doi.org/10.1007/s10048-007-0083-3]
Urtasun, M., Saenz, A., Roudaut, C., Poza, J. J., Urtizberea, J. A., Cobo, A. M., Richard, I., Garcia Bragado, F., Leturcq, F., Kaplan, J. C., Marti Masso, J. F., Beckmann, J. S., Lopez de Munain, A. Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain). Brain 121: 1735-1747, 1998. [PubMed: 9762961] [Full Text: https://doi.org/10.1093/brain/121.9.1735]
Vissing, J., Barresi, R., Witting, N., Van Ghelue, M., Gammelgaard, L., Bindoff, L. A., Straub, V., Lochmuller, H., Hudson, J., Wahl, C. M., Arnardottir, S., Dahlbom, K., Jonsrud, C., Duno, M. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain 139: 2154-2163, 2016. [PubMed: 27259757] [Full Text: https://doi.org/10.1093/brain/aww133]
Zatz, M., Starling, A. Calpains and disease. New Eng. J. Med. 352: 2413-2423, 2005. [PubMed: 15944426] [Full Text: https://doi.org/10.1056/NEJMra043361]