Characterization of LSMEM2 Gene in Patients with Cardiac Conduction Disorder

Abstract

ABSTRACT The contraction and relaxation of the heart muscles is generated by an impulse that is regulated by a specialized system called the Cardiac Conduction System (CCS), organized by specific genes in cardiac cells. Any disruption in the genetic makeup leads to conduction disorders resulting in arrhythmias and sudden cardiac death (SCD). One such disorder is Brugada Syndrome (BrS), a rare genetic conduction disorder. The complete genetic mechanism of the syndrome is still evolving, whereby only 30-35% of the cases are diagnosed with a known genetic mechanism where SCN5A plays a significant role. Utilizing advent tools like Next Generation Sequencing will aid in deciphering the unknown causal variants in rare genetic disorders. In this study, we have identified a novel variant in the LSMEM2 gene in a familial case of BrS utilizing Whole Exome Sequencing (WES). LSMEM2 is an orphan protein that lacks annotation and is highly expressed in cardiac muscle cells. We have used in silico and in vitro approaches to characterize this gene, and the novel variant detected in BrS patients. Additionally, LSMEM2 is found to interact with AMPK, which is a master regulator of cell homeostasis in energy stress. This highlights the hidden pathway of AMPK where LSMEM2 is potentially playing a significant role. Our results show that LSMEM2 could be considered a substantial player in forming the conduction system and underlying diseases in humans. Further functional studies are required to decipher its role in cardiac development and disorders.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences