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Differential involvement of sarcomeric proteins in myofibrillar myopathies: a morphological and immunohistochemical study

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Abstract

Myofibrillar myopathies (MFMs) are rare inherited or sporadic progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. In the current study, we have analyzed histopathological and immunohistochemical characteristics in genetically identified MFMs. We performed a morphological and morphometrical study in a cohort of 24 genetically identified MFM patients (12 desmin, 6 αB-crystallin, 4 ZASP, 2 myotilin), and an extensive immunohistochemical study in 15 of these patients, using both well-known and novel antibodies directed against distinct compartments of the muscle fibers, including Z-disc and M-band proteins. Our morphological data revealed some significant differences between the distinct MFM subgroups: the consistent presence of ‘rubbed-out’ fibers in desminopathies and αB-crystallinopathies, an elevated frequency of vacuoles in ZASPopathies and myotilinopathies, and the presence of a few necrotic fibers in the two myotilinopathy patients. Immunohistochemistry showed that in MFM only a subset of Z-disc proteins, such as filamin C and its ligands myotilin and Xin, exhibited significant alterations in their localization, whereas other Z-disc proteins like α-actinin, myopodin and tritopodin, did not. In contrast, M-band proteins revealed no abnormalities in MFM. We conclude that the presence of ‘rubbed-out’ fibers are a suggestive feature for desminopathy or αB-crystallinopathy, and that MFM is not a general disease of the myofibril, but primarily affects a subgroup of stress-responsive Z-disc proteins.

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Acknowledgments

We are very thankful to Maud Beuvin, Guy Brochier, Mai-Thao Bui, Emmanuelle Lacène, Linda Manéré and Andrée Rouche for their excellent technical support. GF was supported by Grant GGP04088 from the Telethon Foundation-Italy. DF was supported by a grant from the Deutsche Forschungsgemeinschaft. DF and PvdV are members of the German network on muscular dystrophies (MD-NET) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). The PV team was supported by grant ANR-06-MRAR-03901 and research contract no 12986 from the Association Française contre les Myopathies.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière (Pavillon Risler), 47-83, Boulevard de l’Hôpital, 75651, Paris Cedex 13, France

    Kristl G. Claeys, Norma B. Romero, Gisela Stoltenburg & Michel Fardeau

  2. Centre de Référence Neuromusculaire Paris-Est, AP-HP, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Kristl G. Claeys, Anthony Behin, Tanya Stojkovic, Bruno Eymard, Odile Dubourg, Pascal Laforêt, Norma B. Romero, Michel Fardeau & Thomas Voit

  3. Department of Molecular Cell Biology, University of Bonn, Bonn, Germany

    Peter F. M. van der Ven & Dieter O. Fürst

  4. UPMC Paris 6, Paris, France

    Bruno Eymard, Norma B. Romero & Thomas Voit

  5. Service de Neuropathologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Odile Dubourg

  6. Muscle Molecular Biology Group, International Centre of Genetic Engineering and Biotechnology, Trieste, Italy

    Georgine Faulkner

  7. Unité Fonctionnelle de Cardiogénétique et Myogénétique, Service de Biochimie B, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Pascale Richard

  8. EA 300 Stress et Pathologies du Cytosquelette, UFR des Sciences du Vivant, Université, Paris, France

    Patrick Vicart

  9. The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland

    Bjarne Udd

  10. Department of Neurology, Vasa Central Hospital, Vasa, Finland

    Bjarne Udd

  11. Department of Neurology, Tampere University Hospital and Medical School, Tampere, Finland

    Bjarne Udd

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  1. Kristl G. Claeys
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Correspondence to Kristl G. Claeys.

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401_2008_479_MOESM1_ESM.ppt

Supplementary Fig.1: Immunostainings in myotilinopathies. (a-q) Serial transverse sections in myotilin-mutated patient 24. Wide variability in fiber size, internal nuclei, fiber splitting, vacuoles, aggregates and increased interstitial collagen are observed in HE (a) and TRI (b) stained sections. An abnormal staining pattern is found with antibodies against myotilin (c), desmin (d), XinR (e), XinC (f), filamin C (g), ZASP (h), and NCAM (i). (j-n) A normal to very weak abnormal, diffuse staining pattern was observed using antibodies against myopodin (j-k), tritopodin (l), α-actinin (m) and M-protein (n). (o) Ectopic intrasarcoplasmic expression of dystrophin within several fibers is shown, sometimes with (fiber 2) and sometimes without (fiber 1) the presence of vacuoles. An abnormally enhanced staining pattern is also revealed using the antibody against XIRP2 (p-q), shown at a non-serial section. Numbers (1) and (2) indicate the corresponding affected fibers in serial sections. Bars correspond to 100 μm. (PPT 39319 kb)

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Claeys, K.G., van der Ven, P.F.M., Behin, A. et al. Differential involvement of sarcomeric proteins in myofibrillar myopathies: a morphological and immunohistochemical study. Acta Neuropathol 117, 293–307 (2009). https://doi.org/10.1007/s00401-008-0479-7

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  • DOI: https://doi.org/10.1007/s00401-008-0479-7

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