O.12 A new member of the BTB/Kelch family of proteins is mutated in nemaline myopathy type 6 (NEM6)

Abstract

We identified a putative BTB/Kelch protein that is mutated in nemaline myopathy type 6 (NEM6), an autosomal dominant congenital neuromuscular disorder characterized by the presence of nemaline rods and core-like lesions in the skeletal myofibers. Analysis of the Dutch and Australian–Dutch pedigrees previously reported by Gommans et al. [1] and the newly identified Spanish and Australian–Belgian families allowed to narrow the candidate region on chromosome on 15q22.31. Screening of 27 genes within the candidate region led to the identification of a previously uncharacterized NEM6 gene showing missense c.1170G>C (p.K390N) and c.1222C>T (p.R408C) mutations that perfectly co-segregate with the disease in the Spanish, and Dutch, Australian–Dutch and Australian–Belgian families, respectively. Screening of 14 other probands with core-rod myopathies identified a c.742C>A (p.R248S) mutation in another Australian family. The NEM6 mutations were not detected in >250 (p.K390N and p.R408C), or >50 (p.R248S), controls of different ethnic backgrounds. The approximately 1.5-kb mRNA of NEM6 has a single open reading frame encoding a protein with a calculated molecular mass of 49 kDa. The NEM6 protein contains a BTB/POZ domain and five Kelch-like repeats and is expressed strongly in skeletal and cardiac muscle. The BTB/POZ and kelch domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, DNA binding, and cell migration. The functional role of the NEM6 protein in skeletal muscle and pathogenesis of nemaline myopathy are subjects of further studies.