Limb–girdle muscular dystrophy: Diagnostic evaluation, frequency and clues to pathogenesis

Lo, Harriet P.; Cooper, Sandra T.; Evesson, Frances J.; Seto, Jane T.; Chiotis, Maria; Tay, Valerie; Compton, Alison G.; Cairns, Anita; Corbett, A.D.; MacArthur, Daniel G.; Yang, Nan; Reardon, Katrina; North, Klaus

doi:10.1016/j.nmd.2007.08.009

Cited by 102 publications

(72 citation statements)

References 52 publications

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“…Although LGMD2I is the most common form of all LGMDs in Northern Europe, 1 LGMD2A (MIM#253600) is the most prevalent in many European countries, 2 -10 Turkey, 11,12 Brazil, 13 Japan, 14,15 Russia 16 and Australia, 17 with variable frequencies that differ depending on ethnic clusters and geographic origins. Estimates based on molecular data indicate that LGMD2A frequency ranges from about 10% of LGMD cases in the United States 18,19 to 80% in the Basque country and Russia.…”

Section: Introductionmentioning

confidence: 99%

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A

et al. 2008

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Limb-girdle muscular dystrophy (LGMD) 2A (calpainopathy) is the most frequent form of LGMD in many European countries. The increasing demand for a molecular diagnosis makes the identification of strategies to improve gene mutation detection crucial. We conducted both a quantitative analysis of calpain-3 protein in 519 muscles from patients with unclassified LGMD, unclassified myopathy and hyperCKemia, and a functional assay of calpain-3 autolytic activity in 108 cases with LGMD and normal protein quantity. Subsequently, screening of CAPN3 gene mutations was performed using allele-specific tests and simplified SSCP analysis. We diagnosed a total of 94 LGMD2A patients, carrying 66 different mutations (six are newly identified). The probability of diagnosing calpainopathy was very high in patients showing either a quantitative (80%) or a functional calpain-3 protein defect (88%). Our data show a high predictive value for reduced-absent calpain-3 or lost autolytic activity. These biochemical assays are powerful tools for otherwise laborious genetic screening of cases with a high probability of being primary calpainopathy. Our multistep diagnostic approach is rational and highly effective. This strategy has improved the detection rate of the disease and our extension of screening to presymptomatic phenotypes (hyperCKemia) has allowed us to obtain early diagnoses, which has important consequences for patient care and genetic counseling.

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Section: Introductionmentioning

confidence: 99%

How to tackle the diagnosis of limb-girdle muscular dystrophy 2A

et al. 2008

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“…12 In other countries, such as Australia and Italy, the frequency of sarcoglycanopathy is lower (below 20%). 9,34,35 In Europe, North America, Brazil, and India the majority of patients deficient for sarcoglycan proteins has genetic defects in ␣-sarcoglycan (LGMD-2D), a form less frequent in Northern Africa. 9,12,33,36 -38 Analyses of muscle biopsies from LGMD-2D patients carrying ␣-sarcoglycan mutations reveal the absence or severe reduction of all four sarcoglycan subunits.…”

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confidence: 99%

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

Gastaldello

D'Angelo

Franzoso

et al. 2008

The American Journal of Pathology

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Sarcoglycanopathies are progressive muscle-wasting disorders caused by genetic defects of four proteins, ␣-, ␤-, ␥-, and ␦-sarcoglycan, which are elements of a key transmembrane complex of striated muscle. The proper assembly of the sarcoglycan complex represents a critical issue of sarcoglycanopathies, as several mutations severely perturb tetramer formation. Misfolded proteins are generally degraded through the cell's quality-control system; however, this can also lead to the removal of some functional polypeptides. To explore whether it is possible to rescue sarcoglycan mutants by preventing their degradation, we generated a heterologous cell system, based on human embryonic kidney (HEK) 293 cells, constitutively expressing three (␤, ␥, and ␦) of the four sarcoglycans. In these ␤␥␦-HEK cells, the lack of ␣-sarcoglycan prevented complex formation and cell surface localization, wheras the presence of ␣-sarcoglycan allowed maturation and targeting of the tetramer. As in muscles of sarcoglycanopathy patients, transfection of ␤␥␦-HEK cells with disease-causing ␣-sarcoglycan mutants led to dramatic reduction of the mutated proteins and the absence of the complex from the cell surface. Proteasomal inhibition reduced the degradation of mutants and facilitated the assembly and targeting of the sarcoglycan complex to the plasma membrane. These data provide important insights for the potential development of pharmacological therapies for sarcoglycanopathies.

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“…Estimates report a prevalence ranging from 1 in 14,500 to 1 in 123,000 (1)(2)(3). On the basis of immunohistochemical and genetic examinations, the overall frequency of the LGMDs is of 5-70 cases/million population (4)(5)(6)(7)(8)(9). According to the inheritance pattern,…”

Section: Genetic Backgroundmentioning

confidence: 99%