P.472 - Unexpected gene expression findings in the titinopathy mouse model FINmaj-KI using RNA-Seq

Abstract

Heterozygous dominant mutations in the C-terminal part of the sarcomeric protein titin cause tibial muscular dystrophy (TMD; OMIM: #600334). In Finland, the most common mutation is an 11-bp insertion/deletion called FINmaj and homozygosity of the FINmaj mutation cause a much more severe limb-girdle phenotype (LGMD2J; OMIM: #608807). Gene expression changes caused by this mutation have previously been studied in patient muscle biopsies already showing significant muscle pathology and the early changes caused by titin mutations were therefore beyond reach. The mouse model FINmaj-KI makes studies of pre-symptomatic changes feasible. Here, we have studied the gene expression in wild-type, heterozygous and homozygous FINmaj-KI mice at 2 months of age, before the muscle sample show any pathology, using RNA sequencing. The results indicate changes in a variety of cellular pathways including changes in genes encoding extracellular matrix proteins.