O.23 A novel desmin mutation causes autosomal recessive limb girdle muscular dystrophy without features of myofibrillar myopathy

Abstract

Autosomal recessive limb girdle muscular dystrophies (LGMD2s) and congenital muscular dystrophies may overlap at the genetic level, with the same gene being responsible for either a severe form of congenital muscular dystrophy or LGMD2. In this study, we performed genome wide homozygosity mapping and mapped the LGMD2 phenotype to chromosome 2q35-q36.3 in a LGMD2 family. DNA sequence analysis of the highly relevant candidate gene DES revealed a homozygous splice site mutation c.1289–2A > G in the two affected family members. Immunofluorescent staining and western blot analysis showed that the expression and the cytoskeletal network formation of mutant desmin were well preserved in skeletal muscle fibers. Interestingly, the affected individuals do not have the typical features of previously identified patients with desminopathy, neither cardiomyopathy nor the typical histological changes such as disruption of myofibrillar organization, aggregation of intracellular proteins, dislocation and aggregation of membranous organelles. This novel splice site mutation results in addition of 16 amino acids within the tail domain of desmin, which has been suggested to interact with lamin B protein. We also detected a specific disruption of desmin-lamin B interaction in the skeletal muscle of the patient by confocal laser scanning microscopy and highlight the importance of desmin-lamin B interaction in the pathogenesis of LGMD2. This study expands the spectrum of phenotypes associated with DES mutations and identifies a novel LGMD2 subtype.