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Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy.

  • Mavillard, Fabiola1, 2
  • Servian-Morilla, Emilia1, 2
  • Dofash, Lein3
  • Rojas-Marcos, Iñigo1, 4
  • Folland, Chiara3
  • Monahan, Gavin3
  • Gutierrez-Gutierrez, Gerardo5
  • Rivas, Eloy6
  • Hernández-Lain, Aurelio7
  • Valladares, Amador1
  • Cantero, Gloria1
  • Morales, Jose M8
  • Laing, Nigel G3
  • Paradas, Carmen1, 2, 4
  • Ravenscroft, Gianina3
  • Cabrera-Serrano, Macarena1, 2, 3, 4
  • 1 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain. , (Spain)
  • 2 Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, 28220 Madrid, Spain. , (Spain)
  • 3 Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia. , (Australia)
  • 4 Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain. , (Spain)
  • 5 Department of Neurology, Hospital Universitario Infanta Sofia, Universidad Europea de Madrid, Madrid 28702, Spain. , (Spain)
  • 6 Department of Neuropathology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain. , (Spain)
  • 7 Department of Neuropathology, Hospital Universitario 12 de Octubre, Madrid 28041, Spain. , (Spain)
  • 8 Department of Neuroradiology, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain. , (Spain)
Published Article
Oxford University Press
Publication Date
Dec 01, 2023
DOI: 10.1093/brain/awad256
PMID: 37503746


The extracellular matrix (ECM) has an important role in the development and maintenance of skeletal muscle, and several muscle diseases are associated with the dysfunction of ECM elements. MAMDC2 is a putative ECM protein and its role in cell proliferation has been investigated in certain cancer types. However, its participation in skeletal muscle physiology has not been previously studied. We describe 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease. The radiological aspect of muscle involvement resembles that of COL6 myopathies with fat replacement at the peripheral rim of vastii muscles. In this cohort, a subfascial and peri-tendinous pattern is observed in upper and lower limb muscles. Here we show that MAMDC2 is expressed in adult skeletal muscle and differentiating muscle cells, where it appears to localize to the sarcoplasm and myonuclei. In addition, we show it is secreted by myoblasts and differentiating myotubes into to the extracellular compartment. The last exon encodes a disordered region with a polar residue compositional bias loss of which likely induces a toxic effect of the mutant protein. The precise mechanisms by which the altered MAMDC2 proteins cause disease remains to be determined. MAMDC2 is a skeletal muscle disease-associated protein. Its role in muscle development and ECM-muscle communication remains to be fully elucidated. Screening of the last exon of MAMDC2 should be considered in patients presenting with autosomal dominant muscular dystrophy, particularly in those with a subfascial radiological pattern of muscle involvement. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: [email protected].

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