Pluto Bioinformatics

GSE142538: Analyzing Presymptomatic Tissue to Gain Insights into Late-Onset Degenerative Trinucleotide Repeat Disease

Bulk RNA sequencing

How genetic defects trigger late-onset disease is important for understanding disease progression and therapeutic development.Fuchs endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CUG expansion in an intron within theTCF4gene. The mutant intronic CUG RNA is present at 1-2 copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because; 1) Affected tissue is routinely removed during surgery; 2) The expanded CUG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and 3)The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis.Here we use RNA sequencing to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cell-specific manner. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute efficiency of splicing changes are similar in presymptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease. SOURCE: Venkateswara Mootha (vinod.mootha@utsouthwestern.edu) - Mootha Lab UT Southwestern