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Updated: Jul 21, 2025
Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
Published on: May 24, 2016
Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy
Fabiola Mavillard1,2, Emilia Servian-Morilla1,2, Lein Dofash3
1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
Abstract:
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.
Insights
Mutations in the MAMDC2 gene cause a new form of autosomal dominant muscular dystrophy. This discovery highlights MAMDC2 as a skeletal muscle disease-associated protein, crucial for understanding muscle development and extracellular matrix communication.
Area of Science:
- Genetics and Molecular Biology
- Neurology and Musculoskeletal Disorders
Background:
- Extracellular matrix (ECM) proteins are vital for skeletal muscle development and maintenance.
- Dysfunction of ECM elements is linked to various muscle diseases.
- The role of MAMDC2, a potential ECM protein, in skeletal muscle physiology was previously unstudied.
Purpose of the Study:
- To investigate the role of MAMDC2 in skeletal muscle physiology.
- To identify the genetic basis of an autosomal dominant muscular dystrophy.
- To characterize the clinical and radiological features of this novel muscular dystrophy.
Main Methods:
- Genetic analysis of two families with autosomal dominant muscular dystrophy.
- Co-segregation analysis of MAMDC2 variants with the disease phenotype.
- Radiological assessment of muscle involvement.
- Immunohistochemical analysis of MAMDC2 expression in skeletal muscle.
- In vitro studies of MAMDC2 secretion by muscle cells.
Main Results:
- Identified heterozygous truncating variants in the last exon of MAMDC2 co-segregating with autosomal dominant muscular dystrophy in 17 individuals from two families.
- Radiological findings showed a pattern resembling COL6 myopathies, with peripheral fat replacement in vastii muscles and a subfascial/peri-tendinous pattern in limb muscles.
- MAMDC2 is expressed in adult skeletal muscle and differentiating muscle cells, localizing to sarcoplasm and myonuclei.
- MAMDC2 is secreted by myoblasts and myotubes into the extracellular space.
- Loss of the disordered region in the last exon likely causes a toxic effect of the mutant protein.
Conclusions:
- MAMDC2 is a novel skeletal muscle disease-associated protein.
- Truncating variants in MAMDC2 cause autosomal dominant muscular dystrophy with specific radiological features.
- Further research is needed to elucidate the precise disease mechanisms and the role of MAMDC2 in muscle development and ECM-muscle communication.
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