Dr. Anita Simonds - Consultant Respirologist
Royal Brompton and Harefield Hospital, London

Nigel G Laing, Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, B Block QEII Medical Centre, Nedlands, Western Australia 6009, Australia.

My research into nemaline myopathy started in 1989 because of a large South Australian family with dominant nemaline myopathy. This family had ten living affected family members and was the first opportunity to find any gene for nemaline myopathy. In 1992 we demonstrated that the disease gene in the family was within an approximately 27 million base pair region on chromosome 1. In 1995, we demonstrated that the mutated gene in this family was the gene for slow alpha-tropomyosin (TPM3). Tropomyosin is a protein component of the muscle thin filament and this pioneering result moved the nemaline myopathy focus from the Z-disc to the thin filament. We now know of 5 additional thin filament protein genes which when mutated may cause nemaline myopathy: nebulin (NEB - found in 1999); actin (ACTA1 -1999), beta tropomyosin (TPM2 - 2000); slow troponin T (TNNT1 - 2000); cofilin (CFL2 - 2007). Most nemaline myopathy patients have mutations in nebulin, with mutations in actin being the second most common cause of nemaline myopathy and the main cause of the severe cases of nemaline myopathy. Actin mutations were first found in my laboratory and we have over the last few years concentrated on that gene. We now know of over 130 different mutations in actin associated with congenital myopathies. Mutations in actin may cause dominant or recessive diseases, but most patients have new mutations not present in either parent. Since we first found mutations in skeletal actin, we have thought that it might be possible to use cardiac actin, the actin we normally have in our hearts and in our skeletal muscles before we are born, to treat skeletal actin diseases. Recently we identified a number of nemaline myopathy patients with recessive actin disease who, because of the precise mutations they have in their actin gene, have no skeletal actin at all. We showed that these patients have retained cardiac actin instead of skeletal actin in their skeletal muscles and that the patients with the most cardiac actin in their skeletal muscles have done the best. This adds weight to our theory that cardiac actin might be used to treat skeletal actin diseases and we have begun further investigations to test if cardiac actin can replace skeletal actin in experimental models of nemaline myopathy.