Abstract
Background
Mutations in the alpha-sarcoglycan gene cause limb-girdle muscular dystrophy 2D, an autosomal recessive muscle wasting disorder primarily affecting the muscles of the shoulder and pelvic girdles. To date, no previous study has collated all known mutations in alpha-sarcoglycan and mapped these to the associated phenotypes.
Aims
To examine for correlations between mutation locations, or mutation type, and the phenotype caused in all reported mutations in alpha-sarcoglycan.
Methods
We present a systematic literature review examining correlations between mutation locations, or mutation type, and the phenotype caused in all reported cases of limb-girdle muscular dystrophy 2D.
Results
From 134 unique genotypes collated, a strong prevalence of missense mutations (64% of all unique mutations) was found in this gene. Mutation hotspots were noted in exon three and the extracellular domain, with mutation densities varying significantly between both exons and protein domains (p ≤ 0.01). All compound heterozygous limb-girdle muscular dystrophy 2D patients with cardiac involvement contained at least one mutation in exon three, a novel finding. All non-sense mutations in alpha-sarcoglycan give a severe phenotype, as do genotypes involving a combination of exons four and five. This study confirms on a large, diverse cohort the extremely high prevalence of the c.229C > T mutation.
Conclusions
This study demonstrates the vast variation in disease severity seen between patients possessing the same mutation, highlighting the difficulty identifying genotype–phenotype correlations in this condition. Novel findings including the involvement of exon three in all compound heterozygous patients who suffered from cardiomyopathy, and the severity of mutations involving exons four and five may help to guide investigations and therapeutic decisions in an era of personalised medicine.
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References
Ervasti JM, Ohlendieck K, Kahl SD et al (1990) Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345:315–319. https://doi.org/10.1038/345315a0
Petrof BJ, Shrager JB, Stedman HH et al (1993) Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 90:3710–3714. https://doi.org/10.1073/pnas.90.8.3710
Eid Mutlak Y, Aweida D, Volodin A et al (2020) A signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size. Nat Commun 11. https://doi.org/10.1038/s41467-020-14895-9
Roberds SL, Anderson RD, Ibraghimov-Beskrovnaya O, Campbell KP (1993) Primary structure and muscle-specific expression of the 50-kDa dystrophin- associated glycoprotein (adhalin). J Biol Chem 268:23739–23742. https://doi.org/10.1016/s0021-9258(20)80440-2
Lim LE, Duclos F, Broux O et al (1995) β–sarcoglycan: characterization and role in limb–girdle muscular dystrophy linked to 4q12. Nat Genet 11:257–265. https://doi.org/10.1038/ng1195-257
Noguchi S, McNally EM, Othmane KB et al (1995) Mutations in the dystrophin-associated protein γ-sarcoglycan in chromosome 13 muscular dystrophy. Science (80- ) 270:819–822. https://doi.org/10.1126/science.270.5237.819
Straub V, Ettinger AJ, Durbeej M et al (1999) ε-Sarcoglycan replaces α-sarcoglycan in smooth muscle to form a unique dystrophin-glycoprotein complex. J Biol Chem 274:27989–27996. https://doi.org/10.1074/jbc.274.39.27989
Mcnally EM, Yoshida M, Mizuno Y et al (1994) Human adhalin is alternatively spliced and the gene is located on chromosome 17q21. Proc Natl Acad Sci U S A 91:9690–9694. https://doi.org/10.1073/pnas.91.21.9690
Roberds SL, Leturcq F, Allamand V et al (1994) Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 78:625–633. https://doi.org/10.1016/0092-8674(94)90527-4
Nigro V, Piluso G, Belsito A et al (1996) Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein. Hum Mol Genet 5:1179–1186. https://doi.org/10.1093/hmg/5.8.1179
Politano L, Nigro V, Passamano L et al (2001) Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord 11:178–185. https://doi.org/10.1016/S0960-8966(00)00174-7
Eymard B, Romero NB, Leturcq F et al (1997) Primary adhalinopathy (α-sarcoglycanopathy): Clinical, pathologic, and genetic correlation in 20 patients with autosomal recessive muscular dystrophy. Neurology 48:1227–1234. https://doi.org/10.1212/WNL.48.5.1227
Angelini C, Fanin M, Freda MP et al (1999) The clinical spectrum of sarcoglycanopathies. Neurology 52:176–179. https://doi.org/10.1212/wnl.52.1.176
Sandonà D, Betto R (2009) Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects. Expert Rev Mol Med 11
Xie Z, Hou Y, Yu M et al (2019) Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. Orphanet J Rare Dis 14:43. https://doi.org/10.1186/s13023-019-1021-9
Trabelsi M, Kavian N, Daoud F et al (2008) Revised spectrum of mutations in sarcoglycanopathies. Eur J Hum Genet 16:793–803. https://doi.org/10.1038/ejhg.2008.9
Carrié A, Piccolo F, Leturcq F et al (1997) Mutational diversity and hot spots in the α-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D). J Med Genet 34:470–475. https://doi.org/10.1136/jmg.34.6.470
Piccolo F, Roberds SL, Jeanpierre M et al (1995) Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. Nat Genet 10:243–245. https://doi.org/10.1038/ng0695-243
Mora M, Di Blasi C, Barresi R et al (1996) Developmental expression of dystrophin, dystrophin-associated glycoproteins and other membrane cytoskeletal proteins in human skeletal and heart muscle. Dev Brain Res 91:70–82. https://doi.org/10.1016/0165-3806(95)00169-7
Gastaldello S, D’Angelo S, Franzoso S et al (2008) Inhibition of proteasome activity promotes the correct localization of disease-causing α-sarcoglycan mutants in HEK-293 cells constitutively expressing β-, γ-, and δ-sarcoglycan. Am J Pathol 173:170–181. https://doi.org/10.2353/ajpath.2008.071146
Bonuccelli G, Sotgia F, Capozza F et al (2007) Localized treatment with a novel FDA-approved proteasome inhibitor blocks the degradation of dystrophin and dystrophin-associated proteins in mdx mice. Cell Cycle 6:1242–1248. https://doi.org/10.4161/cc.6.10.4182
Bartoli M, Gicquel E, Barrault L et al (2008) Mannosidase I inhibition rescues the human α-sarcoglycan R77C recurrent mutation. Hum Mol Genet 17:1214–1221. https://doi.org/10.1093/hmg/ddn029
Bianchini E, Fanin M, Mamchaoui K et al (2014) Unveiling the degradative route of the V247M a-sarcoglycan mutant responsible for LGMD-2D. Hum Mol Genet 23:3746–3758. https://doi.org/10.1093/hmg/ddu088
Hoch L, Henriques SF, Bruge C et al (2019) Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation. Sci Rep 9. https://doi.org/10.1038/s41598-019-43399-w
Carotti M, Marsolier J, Soardi M et al (2018) Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for limb-girdle muscular dystrophy 2D. Hum Mol Genet 27:969–984. https://doi.org/10.1093/hmg/ddy013
Soheili T, Gicquel E, Poupiot J et al (2012) Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications. Hum Mutat 33:429–439. https://doi.org/10.1002/humu.21659
Acknowledgements
This research is built upon work done by Dr Lauren Taylor and Dr Joel Prescott; many thanks go to them for their contribution.
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Conceptualisation: DM, LC; methodology: DM, LC; data collection: LC; formal analysis and investigation: LC; writing—original draft preparation: LC; writing—review and editing: LC, DM; supervision: DM.
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Carson, L., Merrick, D. Genotype–phenotype correlations in alpha-sarcoglycanopathy: a systematic review. Ir J Med Sci 191, 2743–2750 (2022). https://doi.org/10.1007/s11845-021-02855-1
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DOI: https://doi.org/10.1007/s11845-021-02855-1