Novel genes in skeletal muscle disease

  • Forest, Alistair (Primary Chief Investigator (PCI))
  • Ravenscroft, Gianina (Chief Investigator (CI))
  • Bryson-Richardson, Robert (Chief Investigator (CI))
  • Laing, Nigel G (Chief Investigator (CI))
  • Carninci, Piero (Chief Investigator (CI))

Project: Research

Project Details

Project Description

Mutations of >500 genes are known to cause a range of neuromuscular diseases, however screening of these genes only identifies causative mutations for
~50% of patients. For the undiagnosed patients, whole exome or whole genome sequencing (WES/WGS) can help identify new causative genes. Despite this,
WES often identifies many more candidate disease causing coding sequence variants than can feasibly be verified by functional studies. Using gene
expression profiles from the FANTOM5 consortium we have shown that we can prioritize these candidates and identify new genes mutated in skeletal muscle
disease. Of 83 coding genes that we identified as >1,000-fold enriched in skeletal muscle, 40 have been previously associated with skeletal muscle disease
while a further 53 were not known to cause disease. We have since identified families with mutations in two of these 53 genes – illustrating the power of this
approach. In this project we aim to functionally test the biological role of these novel genes in skeletal muscle biology in vitro (using genome edited myoblast
lines) and in vivo (using zebrafish). Additionally we have recently completed a global map of human long non-coding RNAs (lncRNAs) and have identified a
subset that are specifically expressed in the skeletal muscle lineage, none of which have previously been assessed for roles in normal or diseased muscle
biology. We will also test these novel lncRNAs using genome edited lines. Lastly we will further refine our gene prioritization approaches by incorporating
novel skeletal muscle expression profiles, including profiles of flow sorted, fast and slow-twitch myofibres (based on myosin isoform expression) and
expression profiles of different muscle groups from our collaborators. The ultimate aim of this project is to ensure that all patients with skeletal muscle
diseases receive that fundamental right of an accurate molecular diagnosis.
Effective start/end date1/01/1831/12/20