Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein

Nigro, Vincenzo; Piluso, Giulio; Belsito, Angela; Politano, Luisa; Puca, Annibale Alessandro; Papparella, Serenella; Rossi, Elena; Viglietto, Giuseppe; Esposito, Maria; Abbondanza, Ciro; Medici, Nicola; Molinari, Anna Maria; Nigro, Giovanni; Puca, Giovanni Alfredo

doi:10.1093/hmg/5.8.1179

Cited by 171 publications

(91 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The authors suggested that this d-SG mutation has a dominant negative effect. 10 All together, these data suggest that mutation in d-SG gene is likely to be responsible for the DCM, and muscle weakness could result from potential deleterious synergic effect on muscle function of b-and d-SG mutations. We, like others, found that clinical phenotypes of patients with primary sarcoglycanopathy are heterogeneous and cover a clinical spectrum that is similar to the one resulting from mutations in the DMD gene, though Duchenne-and Becker-like muscular dystrophy are the most frequent phenotypes.…”

Section: Sarcoglycan Gene Mutations M Trabelsi Et Almentioning

confidence: 83%

Revised spectrum of mutations in sarcoglycanopathies

et al. 2008

View full text Add to dashboard Cite

To define the spectrum of mutations in a-, b-, c-, and d-sarcoglycan (SG) genes, we analyzed these genes in 69 probands with clinical and biological criteria compatible with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. For 48 patients, muscle biopsies were available and multiplex western blot analysis of muscle proteins showed significant abnormalities of a-and c-SG. Our diagnostic strategy includes multiplex western blot, sequencing of SG genes, multiplex quantitative-fluorescent PCR and RT-PCR analyses. Mutations were detected in 57 patients and homozygous or compound heterozygous mutations were identified in 75% (36/48) of the patients with abnormal western blot, and in 52% (11/21) of the patients without muscle biopsy. Involvement of a-SG was demonstrated in 55.3% of cases (26/47), whereas c-and b-SG were implicated in 25.5% (12/47) and in 17% (8/47) of cases, respectively. Interestingly, we identified 25 novel mutations, and a significant proportion of these mutations correspond to deletions (identified in 14 patients) of complete exon(s) of a-or c-SG genes, and partial duplications (identified in 5 patients) of exon 1 of b-SG gene. This study highlights the high frequency of exonic deletions of a-and c-SG genes, as well as the presence of a hotspot of duplications affecting exon 1 of the b-SG gene. In addition, protein analysis by multiplex western blot in combination with mutation screening and genotyping results allowed to propose a comprehensive and efficient diagnostic strategy and strongly suggested the implication of additional genes, yet to be identified, in sarcoglycanopathy-like disorders.

show abstract

Section: Sarcoglycan Gene Mutations M Trabelsi Et Almentioning

confidence: 83%

Revised spectrum of mutations in sarcoglycanopathies

et al. 2008

View full text Add to dashboard Cite

show abstract

“…After secondary antibodies incubations, cells were washed with PBS and then fixed for 15 minutes with 4% paraformaldehyde in PBS (PFA). For immunofluorescence analysis, cells were fixed with 4% PFA, washed with 50 mmol/L NH 4 Cl, and then permeabilized with 0.5% Triton X-100. Permeabilized cells were then probed with the selected antibodies as above described.…”

Section: Confocal Immunofluorescence Analysis Of Cellsmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…[1][2][3][4][5][6][7][8] Mutations in four genes encoding sarcoglycan proteins (␣-, ␤-, ␥-and ␦-SG) are responsible for various forms of autosomal recessive limb-girdle muscular dystrophy (LGMD 2D, 2E, 2C and 2F, respectively). [9][10][11][12][13][14][15][16] This heterogeneous group of diseases nevertheless shares a common feature in that a primary deficiency of any of the sarcoglycan proteins leads to the reduction or the absence of all other members of the SG-SSPN complex. 17 In non-consanguineous populations, ␣-sarcoglycan deficiency is the most frequent cause of autosomal recessive LGMD with a sarcoglycan defect (sarcoglycanopathy).…”

Section: Introductionmentioning

confidence: 99%

Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice

et al. 2000

View full text Add to dashboard Cite

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is the most common cause of LGMD with a sarcoglycan defect. We recently engineered a murine model for this progressive disease and we investigated the possibility of preventing the development of muscular dystrophy in these animals by adenovirus-mediated gene transfer of human ␣-sarcoglycan.Here we report that a single intramuscular injection of a first generation adenovirus into the skeletal muscle of neonate mice led to sustained expression of ␣-sarcoglycan at the sarcolemma of transduced myofibers for at least 7 months. The morphology of transduced muscles was consequently pre-

show abstract

Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein

Cited by 171 publications

References 38 publications

Revised spectrum of mutations in sarcoglycanopathies

Revised spectrum of mutations in sarcoglycanopathies

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

Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice

Contact Info

Product

Resources

About