Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy

Liu, Jing; Akiyama, Masashi; Illa, Isabel; Wu, Cunle; Fardeau, Michel; Angelini, C.; Serrano, Carmen; Urtizberea, J. Andoni; Hentati, Fayçal; Hamida, M. Ben; Bohlega, Saeed; Culper, Edward J.; Amato, Anthony A.; Bossie, Karen; Oeltjen, Joshua; Bejaoui, Khemissa; McKenna‐Yasek, Diane; Hosler, Betsy A.; Schurr, Erwin; Arahata, Kiichi; Jong, Pieter J. de; Brown, Robert H.

doi:10.1038/1682

Cited by 819 publications

(660 citation statements)

References 33 publications

(25 reference statements)

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“…Mutations in dysferlin are responsible for the progressive autosomal recessive muscular dystrophies Miyoshi myopathy (1), limb girdle muscular dystrophy type 2B (2), and distal anterior compartment myopathy (3).…”

mentioning

confidence: 99%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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Background: Dysferlin encoded by mis-sense alleles is rapidly degraded in skeletal muscle. Results: Proteasomal inhibitors increase dysferlin levels, restore membrane repair and myotube formation in patient-derived myoblasts harboring mis-sense mutated dysferlin. Conclusion: Proteasomal inhibition restores function of mis-sense mutated dysferlin. Significance: Inhibiting the degradation of mis-sense mutated dysferlin may be a therapeutic strategy for dysferlinopathies with certain mis-sense mutations.

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mentioning

confidence: 99%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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“…We previously reported reduced sarcolemmal staining of affixin in dysferlin deficient skeletal muscles, and confirmed the association between affixin and dysferlin by an immunoprecipitation study [8]. Dysferlin is a sarcolemmal protein and its deficiency causes Miyoshi myopathy and limb girdle muscular dystrophy type 2B [9,10]. Based on the observation of Abbreviations: ILK, integrin-linked kinase; PIX, PAK-interactive exchange factor; C2C12-affixin, stable C2C12 cell line expressing T7-tagged human affixin; GEF, guanine nucleotide exchange factor; GST, gulutathione S-transferase; CH, caponin-homology; DH, Dbl-homology; PH, pleckstrin-homology; PAK, p21-activated kinase; CHO, Chinese hamster ovary dysferlin accumulation at wounded sarcolemmal sites, dysferlin is suggested to have an important role in Ca 2+ -induced membrane repair [11].…”

Section: Introductionsupporting

confidence: 66%

Affixin activates Rac1 via βPIX in C2C12 myoblast

et al. 2008

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Affixin/b-parvin is an integrin-linked kinase (ILK)-binding focal adhesion protein highly expressed in skeletal muscle and heart. To elucidate the possible role of affixin in skeletal muscle, we established stable C2C12 cell line expressing T7-tagged human affixin (C2C12-affixin cells). Exogenous expression of affixin promotes lamellipodium formation where affixin, ILK ap21-activated kinase (PAK)-interactive exchange factor (PIX) and bPIX accumulate. The association of affixin and bPIX was confirmed by immunoprecipitation and pull down assay. In C2C12-affixin cells, an increased level of activated Rac1 but not Cdc42 was observed, and mutant bPIX lacking guanine nucleotide exchange factor activity inhibited lamellipodium formation. These results suggest that affixin is involved in reorganization of subsarcolemmal cytoskeletal actin by activation of Rac1 through a and bPIXs in skeletal muscle.

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“…Dysferlinopathies (LGMD2B and Miyoshi myopathy) include autosomal‐recessive muscle diseases caused by pathogenic variants in dysferlin gene ( DYSF ), characterized by proximal muscle weakness, difficulty in running, climbing, increased fatigue 44, 45…”

Section: Discussionmentioning

confidence: 99%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

130

165

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ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

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Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy

Cited by 819 publications

References 33 publications

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Affixin activates Rac1 via βPIX in C2C12 myoblast

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

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