Browsing by Author "Natraj Gayathri, Swethaa"

The TTN gene is composed of 364 exons (363 coding) and encodes for titin, the largest protein in nature. Pathogenic TTN variants result in a wide spectrum of skeletal muscle and cardiac disorders known as Titinopathies. These differ in inheritance patterns, onset age, disease course and severity. The biological mechanisms underlying disease-causing variants specific to titinopathy patients are still elusive. Investigating gene signatures causing the biological pathomechanisms is crucial for understanding genotype-phenotype corelations. RNA-sequencing emerges as a valuable technique for analysing transcriptomic data and exploring gene expression profiles of patient and control samples. To elucidate common pathomechanisms in titinopathies, including adult tibial muscular dystrophy (TMD) due to heterozygous FINmaj variant, and biallelic recessive titinopathies, an extensive differential gene expression (DGE) analysis was conducted using three RNA cohorts from human muscle biopsies. The cohorts involved two polyA enriched and one rRNA depleted batch-corrected cohort. Human DGE analysis identified 265 commonly upregulated genes and 147 commonly downregulated genes in the titinopathy cohorts. A significant downregulation of TTN expression levels was observed in one of the cohorts. To validate and understand the biological significance of these findings, data from a mouse model was incorporated with homozygous Ttn FINmaj variants. Common genes among all cohorts accounted for the structural integrity of the extracellular matrix. This study indicates the pathomechanisms for a skeletal muscle pathology and discusses the future steps in efficiently performing RNA-Seq for titinopathies.