Researchers discover underlying cause of hereditary muscle disease

Researchers at Karolinska Institutet have discovered the underlying cause of a hereditary muscle disease first characterised in a Swedish family in 1980. It proves to be the first identified disease caused by defective myoglobin, the protein that transports oxygen in muscle cells. The study is published in Nature Communications.

Sarcoplasmic body myopathy (SBM) was first characterised in a large Swedish family by Edström et al in 1980, described as a novel late onset distal myopathy with characteristic sarcoplasmic inclusions. The disease manifests in adulthood with proximal weakness that progresses to involve distal muscles and causes respiratory and, in some patients, cardiac failure.

All had the same mutation

Using modern techniques for genome analysis, researchers at Karolinska Institutet and SciLifeLab in Sweden, in collaboration with colleagues in Perth, Australia and Barcelona, Spain, report that they have found the cause of the disease. Six large unrelated European families were studied, including the first Swedish family. The researchers found that all affected individuals had the same mutation in the myoglobin gene, causing one amino acid replacement in the protein.

The two closely related proteins myoglobin and haemoglobin transports oxygen in muscle cells and red blood cells, respectively, and were the first globular proteins structurally resolved by X-ray crystallography, an achievement resulting in a Nobel Prize in Chemistry in 1962.

"Inherited defects of haemoglobin, haemoglobinopathies, resulting in anaemia are well known causes of human disease, but defects of its muscular counterpart, myoglobin, have been unknown until now," says Martin Engvall, PhD student at the Department of Molecular Medicine and Surgery, Karolinska Institutet and shared first author of the new study.

Acquires novel function

In addition to its function in oxygen transport, myoglobin is implicated in the control of so-called redox pathways in skeletal and cardiac muscle cells, acting as scavenger of reactive oxygen species and nitric oxide metabolism. The mutated protein has altered binding of oxygen and heme, but the exact mechanisms by which the mutation causes muscle degeneration are not known. However, as the same mutation is found in all known families, the disease is likely caused by a novel function acquired by the mutant protein, rather than resulting from loss of its normal function.

"This means that a potential therapeutic strategy would be to suppress expression of the mutant version of the gene using e.g. antisense technology, an approach that has recently been successful in other rare inherited diseases," says Anna Wedell, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and shared last author of the study.