C.P.13 The clinical spectrum of entities caused by mutations in the nebulin gene

Abstract

Nebulin is one of the main components of the thin filament of the muscle sarcomere and the gene encoding nebulin (NEB) is, with its 183 exons, one of the biggest genes in the human genome. Mutations in NEB are the most common cause of autosomal recessive nemaline myopathy (NM), which is diagnosed on the basis of muscle weakness and protein aggregates called nemaline bodies in the muscle fibres of the patients. In 2007 we published NEB mutations in four Finnish distal myopathy families with no readily detectable nemaline bodies in their biopsies and in 2011 we described two NM patients with distal muscle weakness. In addition, we have identified NEB mutations in two core-rod myopathy patients; the first one was described in 2009. Usually patients with NEB mutation have type 1 predominance, but we have encountered two patients with type 2 predominance. To date, we have identified more than 140 mutations in NEB in some 100 families. There are no clear mutational hotspots, and mutations are rarely recurrent among the usually compound heterozygous patients. The first large deletion in NEB was published by Anderson et al. in 2004 and to date we have identified three additional large deletions in NM families using a self-designed mutational microarray. Mutations in NEB can cause a variety of different phenotypes with differences in distribution of muscle weakness, severity and histological findings. Our novel combination of methods facilitates mutation identification in the enormous NEB gene, permitting more distinct genotype-phenotype correlations and possibly the discovery of further entities caused by mutation of NEB.