2026-09-18T18:56:38Zhttps://helda.helsinki.fi/server/oai/request

oai:helda.helsinki.fi:10138/5777782026-03-27T00:31:36Zcom_10138_18086com_10138_17738col_10138_18088

Helsingin yliopisto, Bio- ja ympäristötieteellinen tiedekunta University of Helsinki, Faculty of Biological and Environmental Sciences Helsingfors universitet, Bio- och miljövetenskapliga fakulteten Natraj Gayathri, Swethaa Marco Savarese, Per-Harald Jonson 2024 URN:NBN:fi:hulib-202406253234 http://hdl.handle.net/10138/577778 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. eng Helsingin yliopisto University of Helsinki Helsingfors universitet Titin muscle RNA-Seq differential gene expression titinopathy Genetiikka ja genomiikka Genetics and genomics Genetik och genomik Genetiikan ja molekulaaristen biotieteiden maisteriohjelma Master's Programme in Genetics and Molecular Biosciences Magisterprogrammet i genetik och molekylära biovetenskaper Identifying biological pathomechanisms of TTN-affected myopathies using RNA-Sequencing data pro gradu -tutkielmat master's thesis pro gradu-avhandlingar URN:NBN:fi:hulib-202406253234 open.access