VP.81 In vivo modulation of novel genetic modifiers for LAMA2-RD

Abstract

Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is caused by mutations in the LAMA2 gene, which encodes for the α2 subunit of laminin-211. Patients with complete laminin-211 deficiency show a clinically homogeneous and severe phenotype. To date, only one atypical patient with complete laminin-211 deficiency and a remarkably mild phenotype has been reported. Strikingly, the atypical patient and its severely affected sibling carry the same <i>LAMA2</i> loss-of-function mutation, and both lack laminin-211 expression in muscle. Since laminin-211 is not present in either sibling, we hypothesize that there is a rare genetic modifier in the atypical sibling that compensates for laminin-211 absence in muscle via a novel mechanism. We performed unbiased muscle RNA-sequencing and identified genes differentially expressed in the atypical patient compared to unrelated LAMA2-RD patients and healthy controls. Transcriptome data were complemented by the analysis of whole genome sequencing data of both siblings. We identified differentially expressed genes potentially regulated by very rare DNA polymorphisms uniquely present in the atypical sibling. These genes affect pathways commonly dysregulated in LAMA2-RD, such as energy metabolism, regeneration, inflammation and fibrosis, and represent candidate modifier gene(s)/pathway(s) that could provide a novel therapeutic approach and ameliorate LAMA2-RD severity. We are currently testing the most promising candidates in vivo in a LAMA2-knockout zebrafish model that recapitulates LAMA2-RD. In particular we are assessing the potential for these protective modifier(s) to improve muscle morphology and improve the phenotype in the diseased animals. Outcomes of this project will add new knowledge about the molecular aspects of this disorder, shed light on novel mechanisms involved in attenuating LAMA2-RD severity and potentially lead to the development of new therapeutic strategies.