Alternative titles; symbols
HGNC Approved Gene Symbol: SGCA
SNOMEDCT: 715340002; ICD10CM: G71.0341;
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:50,166,005-50,175,928 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.33 | Muscular dystrophy, limb-girdle, autosomal recessive 3 | 608099 | Autosomal recessive | 3 |
The dystrophin-glycoprotein complex (DGC) comprises a group of proteins that are critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Components of the DGC include dystrophin (300377), which is deficient in Duchenne muscular dystrophy (DMD; 310200); syntrophins (e.g., 600026); dystroglycans (128239); and sarcoglycans, such as adhalin, a 50-kD transmembrane protein (Roberds et al., 1993).
Roberds et al. (1993) cloned cDNA encoding 50-DAG from rabbit skeletal muscle. The deduced amino acid sequence of the gene product predicted a 387-amino acid protein with a 17-amino acid signal sequence, 1 transmembrane domain, and 2 potential sites of N-linked glycosylation. Affinity-purified antibodies against rabbit 50-DAG fusion proteins or synthetic peptides specifically recognized a 50-kD protein in skeletal muscle sarcolemma and the 50-kD component of the dystrophin glycoprotein complex. In contrast to dystroglycan, which is expressed in a wide variety of muscle and nonmuscle tissues, 50-DAG was expressed only in skeletal and cardiac muscles and in selected smooth muscles. Roberds et al. (1993) found 50-DAG mRNA in muscle from mdx mice and DMD humans, both with mutations in the dystrophin gene, indicating that the downregulation of this protein in these disease states is probably a posttranslational event.
Roberds et al. (1994) isolated human adhalin cDNA from a human skeletal muscle library and determined the sequence of the gene. They found that human and rabbit adhalin are 86% identical at the amino acid level. Northern blot analysis showed that human adhalin mRNA was most abundant in skeletal muscle, but also expressed in cardiac muscle, and, at much lower levels, in lung. Adhalin mRNA was not detected in brain.
Roberds et al. (1994) determined that the SGCA gene contains 10 exons.
By PCR applied to a panel of human/rodent somatic cell hybrids and DNAs from cell lines with deletion of various parts of chromosome 17, Roberds et al. (1994) mapped the SGCA gene to 17q12-q21.33. McNally et al. (1994) likewise mapped the SGCA gene to 17q21.
McNally et al. (1994) reported that adhalin mRNA from cardiac muscle is shorter than that from skeletal muscle and lacks the base sequence encoding the transmembrane domain. They found lower expression of the ADL gene in cardiac muscle, which may explain the less severe cardiac dysfunction in some patients with adhalin-deficient muscular dystrophy (LGMDR3; 608099). The expression of both adhalin splice forms was exclusively restricted to striated muscle, unlike other components of the dystrophin-glycoprotein complex. The authors speculated that the absence of mental retardation in adhalin-deficient muscular dystrophy is most likely explained by the absence of adhalin expression in the brain.
Matsumura et al. (1992) found a specific deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. The findings suggested that a loss of dystrophin-associated glycoproteins in the sarcolemma is a common denominator in the pathologic processes leading to muscle cell necrosis in various forms of muscular dystrophy.
In a large French family with a mild form of adhalin-deficient limb-girdle muscular dystrophy (LGMDR3; 608099), previously symbolized LGMD2D, Romero et al. (1994) identified mutations in the adhalin gene (600119.0001-600119.0002). The family was nonconsanguineous and affected members were compound heterozygotes, with one mutation coming from each parent. In 10 families from Europe and North Africa with LGMD2D, Piccolo et al. (1995) described several additional mutations (null and missense) in the adhalin gene (see, e.g., 600119.0003). Patients with null mutations were the most severely affected.
Carrie et al. (1997) studied a series of 20 unrelated LGMD2D families with 14 different mutations in the alpha-sarcoglycan gene. Along with the mutations previously reported, this brought their cohort of patients with alpha-sarcoglycanopathy to a total of 31 unrelated patients, carrying 25 different mutations. The missense mutations resided in the extracellular domain of the protein. Five of 15 missense mutations, carried by unrelated subjects on different haplotypes and of widespread geographic origins, account for 58% of the mutated chromosomes with a striking prevalence of the R77C (600119.0003) substitution (32%). The severity of the disease varied strikingly and correlated at least in part with the amount of residual protein and the type of mutation. The recurrent R284C substitution (600119.0005) was associated with a benign disease course. Almost all patients presented with a limb-girdle muscular dystrophy phenotype of variable severity. Neither heart involvement nor mental retardation was present.
Bartoli et al. (2008) found that SGCA with the R77C mutation was retained in the endoplasmic reticulum (ER), where it formed aggregates. Surface expression of mutant SGCA could be rescued by inhibiting its degradation via proteasome-mediated ER-associated degradation (ERAD) or by inhibiting mannosidase I (MAN1B1; 604346), an ER enzyme that directs misfolded glycoproteins toward ERAD.
Trabelsi et al. (2008) identified biallelic mutations in sarcoglycan genes in 46 (67%) of 69 patients with a clinical diagnosis of autosomal recessive LGMD. Twenty-six (56.5%) patients had SGCA mutations, 8 (17.3%) had SGCB (600900) mutations, and 12 (26%) had SGCG (608896) mutations. A total of 23 different mutations, including 10 novel mutations, were identified in SGCA, with a relatively high frequency of mutations in exon 3 (13 of 26, 50%) and exon 5 (6 of 26, 23%).
To investigate mechanisms in the pathogenesis of cardiomyopathy associated with mutations of the dystrophin-glycoprotein complex, Coral-Vazquez et al. (1999) analyzed genetically engineered mice deficient for either the Sgca or Sgcd (601411) gene. They found that only Sgcd-null mice developed cardiomyopathy with focal areas of necrosis as the histologic hallmark in cardiac and skeletal muscle. The authors observed absence of the sarcoglycan-sarcospan (SG-SSPN) complex in skeletal and cardiac membranes in both animal models. These data indicated that disruption of the SG-SSPN complex in vascular smooth muscle perturbs vascular function, which initiates cardiomyopathy and exacerbates muscular dystrophy.
Imamura et al. (2005) established several transgenic mouse lines that overexpressed Sgce (604149) in skeletal muscle. Overexpression in normal mice resulted in substitution of Sgce for Sgca in the sarcoglycan complex of skeletal muscle without any obvious abnormalities. Mice overexpressing Sgce were crossed with Sgca-deficient mice, and Sgca-deficient mice overexpressing Sgce exhibited no skeletal muscle cell membrane damage or abnormal contraction. Imamura et al. (2005) suggested that overexpression of SGCE may represent a therapeutic strategy for treatment of LGMD2D.
Kobuke et al. (2008) and Bartoli et al. (2008) independently created mice expressing Sgca with a his77-to-cys (H77C) mutation, corresponding to the common human SGCA mutation R77C (600119.0003). Both groups found that mice homozygous for H77C appeared normal and developed no signs of muscular dystrophy at either the histologic or physiologic levels. Kobuke et al. (2008) found that human SGCA with the R77C mutation was correctly processed and transported to the sarcolemma of Sgca -/- mice, where it rescued the dystrophic phenotype of Sgca -/- mice. Kobuke et al. (2008) and Bartoli et al. (2008) concluded that SGCA is subject to species-specific trafficking.
The 50-kD dystrophin-associated glycoprotein was named adhalin from the Arabic adhal (muscle). As the first component of the sarcoglycan complex to be identified, adhalin is also referred to as alpha-sarcoglycan. Beta-sarcoglycan (600900) was the second component to be identified.
In a nonconsanguineous French family with limb-girdle muscular dystrophy type 2D (LGMDR3; 608099), Roberds et al. (1994) found that affected members were compound heterozygotes for a maternally derived arg98-to-his (R98H) mutation and a paternally derived val175-to-ala (V175A) mutation (600119.0002).
For discussion of the val175-to-ala (V175A) mutation in the SGCA gene that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2D (LGMDR3; 608099) by Roberds et al. (1994), see 600119.0001.
In a German family with Duchenne-like muscular dystrophy of intermediate severity (LGMDR3; 608099), Piccolo et al. (1995) found a homozygous CGC-to-TGC transition in exon 3 of the SGCA gene, resulting in an arg77-to-cys (R77C) substitution. The same mutation was found in the heterozygous state in 2 apparently unrelated French families in which the affected individuals were compound heterozygotes. In a note added in proof, Piccolo et al. (1995) commented that out of a total of 46 mutated chromosomes from unrelated families in Europe and the US, 11 had the R77C mutation. Four patients were homozygous for the mutation.
Passos Bueno et al. (1995) identified the same mutation in 3 Brazilian families with a relatively mild form of LGMD2D.
In a Japanese patient with autosomal recessive childhood-onset muscular dystrophy from a consanguineous family, Kawai et al. (1995) found homozygosity for the R77C mutation. Muscle biopsy showed complete absence of adhalin.
Bartoli et al. (2008) found that SGCA with the R77C mutation was retained in the endoplasmic reticulum (ER), where it formed aggregates. Surface expression of mutant SGCA could be rescued by inhibiting its degradation via proteasome-mediated ER-associated degradation (ERAD) or by inhibiting mannosidase I (MAN1B1; 604346), an ER enzyme that directs misfolded glycoproteins toward ERAD.
Kawai et al. (1995) reported homozygosity for a double mutation in the ADL gene in a Japanese family in which 5 individuals in 2 sibships over 2 successive generations were affected with limb-girdle muscular dystrophy type 2D (LGMDR3; 608099). In the case of each sibship, the parents were related as first cousins. The mutation consisted of a 410A-G transition, resulting in a glu137-to-gly (E137G) substitution. In addition, there was a 15-bp insertion between nucleotides 408 and 409 (between codons 136 and 137), which added 5 amino acids in-frame to the gene product. Muscle biopsy of affected patients showed complete absence of adhalin. The patients did not suffer from severe cardiac dysfunction or mental retardation, which are features of DMD. Indeed, one patient showed no symptoms of cardiac failure, even at 56 years of age.
In a 40-year-old woman with mild limb-girdle type muscular dystrophy (LGMDR3; 608099) that responded to steroid administration, Angelini et al. (1998) found a homozygous 850C-T change, resulting in an arg284-to-cys (R284C) substitution. Her asymptomatic 35-year-old brother had the same homozygous mutation.
In an 18-year-old Russian patient with limb-girdle muscular dystrophy type 2D (LGMDR3; 608099) who was initially diagnosed with Duchenne muscular dystrophy (310200), Schara et al. (2001) identified compound heterozygosity for a tyr134-to-stop (Y134X) substitution and the R77C mutation (600119.0003) in the SGCA gene. Schara et al. (2001) reinforced the need for molecular genetic analysis to establish the correct diagnosis in patients with limb-girdle muscular dystrophy.
In 2 Albanian sibs, born of consanguineous parents, with limb-girdle muscular dystrophy type 2D (LGMDR3; 608099), Babameto-Laku et al. (2011) identified a homozygous 574C-T transition in exon 5 of the SGCA gene, resulting in an arg192-to-ter (R192X) substitution. Each unaffected parent was heterozygous for the mutation. The 7-year-old sister showed difficulty climbing stairs and getting up at age 3 years. This proximal muscle weakness progressed, with frequent falls, waddling gait, toe walking, and difficulty raising the arms above the head. She also had calf pseudohypertrophy, Achilles tendon contractures, mild scapular winging, and hyperlordosis. Her younger brother started to manifest similar clinical symptoms of proximal muscle weakness between 2 and 3 years of age. Both patients had increased serum creatine kinase, and muscular biopsy showed dystrophic changes with decreased staining for alpha- and gamma-sarcoglycan (SGCG; 608896). The phenotype in both patients was severe enough to clinically suggest Duchenne muscular dystrophy (310200).
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