P.9.8 Nemaline myopathy: Mutations in alternatively spliced exons of the nebulin gene

Abstract

One of the key components in stabilizing and determining the lengths of the actin filaments of the skeletal muscle sarcomere and in the neurons of the brain is the gigantic protein nebulin. Its size varies from 600 to 900kDa and correlates with the length of the actin filaments. A huge variation in length is produced by differential usage of the alternatively spliced exons 63–66, 143–144 and 166–177, among the 183 exons of the nebulin gene (<i>NEB</i>). Exons 63–66 are always expressed together as a block, while exons 143 and 144 give rise to two different transcripts varying between muscle types and in different developmental stages. Exons 166–177 are spliced independently. Over 150 recessive, mostly nemaline myopathy- (NM) causing mutations, but also mutations causing core-rod and distal myopathies have been identified to date; homozygous or both of the compound heterozygous mutations have been identified in 106 probands of the Helsinki cohort. Of these probands, 23 have a mutation in an alternatively spliced exon. Interestingly, at least twelve of them have clinical features unusual in NM, and two have core-rod myopathy. Vice versa, many probands in the Helsinki cohort with <i>NEB</i> mutations and unusual features such as core structures seen in their muscle biopsies have at least one of their two compound heterozygous mutations located in an alternatively spliced exon; three probands have mutations in exons 63–66, three in exons 143 or 144, and ten in exons 167–177. Three of these probands have both of their mutations in alternatively spliced exons. Further studies on the expression of alternatively spliced exons in different muscles combined with the clinical data of the patients with mutations in alternatively spliced exons might provide insights into the role and importance of these exons in different muscles and developmental stages, and explain some phenotypic features. The work is ongoing.