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

Fabiola Mavillard, Emilia Servian-Morilla, Lein Dofash, Iñigo Rojas-Marcos, Chiara Folland, Gavin Monahan, Gerardo Gutierrez-Gutierrez, Eloy Rivas, Aurelio Hernández-Lain, Amador Valladares, Gloria Cantero, Jose M. Morales, Nigel G. Laing, Carmen Paradas, Gianina Ravenscroft, Macarena Cabrera-Serrano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article numberawad256
Pages (from-to)5235-5248
Number of pages14
Issue number12
Early online date25 Oct 2023
Publication statusPublished - 1 Dec 2023

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