Dataset Information

Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.

ABSTRACT:

Objectives

Rippling muscle disease (RMD) is characterized by muscle stiffness, muscle hypertrophy, and rippling muscle induced by stretching or percussion. Hereditary RMD is due to sequence variants in the CAV3 and PTRF/CAVIN1 genes encoding Caveolin-3 or Cavin-1, respectively; a few series of patients with acquired autoimmune forms of RMD (iRMD) associated with AChR antibody-positive myasthenia gravis and/or thymoma have also been described. Recently, MURC/caveolae-associated protein 4 (Cavin-4) autoantibody was identified in 8 of 10 patients without thymoma, highlighting its potential both as a biomarker and as a triggering agent of this pathology. Here, we report the case of a patient with iRMD-AchR antibody negative associated with thymoma.

Methods

We suspected a paraneoplastic origin and investigated the presence of specific autoantibodies targeting muscle antigens through a combination of Western blotting and affinity purification coupled with mass spectrometry-based proteomic approaches.

Results

We identified circulating MURC/Cavin-4 autoantibodies and found strong similarities between histologic features of the patient's muscle and those commonly reported in caveolinopathies. Strikingly, MURC/Cavin-4 autoantibody titer strongly decreased after tumor resection and immunotherapy correlating with complete disappearance of the rippling phenotype and full patient remission.

Discussion

MURC/Cavin-4 autoantibodies may play a pathogenic role in paraneoplastic iRMD associated with thymoma.

SUBMITTER: Svahn J

PROVIDER: S-EPMC9756388 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.

Svahn Juliette J Coudert Laurent L Streichenberger Nathalie N Kraut Alexandra A Gravier-Dumonceau-Mazelier Alice A Rotard Ludivine L Calemard-Michel Laurence L Menassa Rita R Errazuriz-Cerda Elisabeth E Chalabreysse Lara L Osseni Alexis A Vial Christophe C Jomir Laurentiu L Tronc François F Le Duy Do D Bernard Emilien E Gache Vincent V Couté Yohann Y Jacquemond Vincent V Schaeffer Laurent L Leblanc Pascal P

Neurology(R) neuroimmunology & neuroinflammation 20221215 1

<h4>Objectives</h4>Rippling muscle disease (RMD) is characterized by muscle stiffness, muscle hypertrophy, and rippling muscle induced by stretching or percussion. Hereditary RMD is due to sequence variants in the <i>CAV3</i> and <i>PTRF/CAVIN1</i> genes encoding Caveolin-3 or Cavin-1, respectively; a few series of patients with acquired autoimmune forms of RMD (iRMD) associated with AChR antibody-positive myasthenia gravis and/or thymoma have also been described. Recently, MURC/caveolae-associa ...[more]

PMID: 36522170

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Project description:ImportanceImmune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking.ObjectiveTo describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics.Design, setting, and participantsThis retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months.ExposuresDiagnosis of iRMD.Main outcomes and measuresDetection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.ResultsSeven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change.Conclusions and relevanceThe findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

Project description:Background Ischemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. MURC (muscle-restricted coiled-coil protein)/Cavin-4 (caveolae-associated protein 4), which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown. Methods and Results The systems network genomic analysis based on PC-corr network inference on microarray data between wild-type and MURC knockout mouse hearts predicted a network of discriminating genes associated with reactive oxygen species. To demonstrate the prediction, we analyzed I/R-injured mouse hearts. MURC deletion decreased infarct size and preserved heart contraction with reactive oxygen species-related molecule EGR1 (early growth response protein 1) and DDIT4 (DNA-damage-inducible transcript 4) suppression in I/R-injured hearts. Because PC-corr network inference integrated with a protein-protein interaction network prediction also showed that MURC is involved in the apoptotic pathway, we confirmed the upregulation of STAT3 (signal transducer and activator of transcription 3) and BCL2 (B-cell lymphoma 2) and the inactivation of caspase 3 in I/R-injured hearts of MURC knockout mice compared with those of wild-type mice. STAT3 inhibitor canceled the cardioprotective effect of MURC deletion in I/R-injured hearts. In cardiomyocytes exposed to hydrogen peroxide, MURC overexpression promoted apoptosis and MURC knockdown inhibited apoptosis. STAT3 inhibitor canceled the antiapoptotic effect of MURC knockdown in cardiomyocytes. Conclusions Our findings, obtained by prediction from systems network genomic analysis followed by experimental validation, suggested that MURC modulates cardiac I/R injury through the regulation of reactive oxygen species-induced cell death and STAT3-meditated antiapoptosis. Functional inhibition of MURC may be effective in reducing cardiac I/R injury.

Dataset Information

Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.

Objectives

Methods

Results

Discussion

Publications

Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.

Similar Datasets

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