Extended Data Fig. 3: Expression of KCNQ2∆E5 is highly specific to ALS/FTD and TDP-43 pathology.
From: TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD
(a) Reads mapping to KCNQ2∆E5 in RNA-seq datasets stratified by disease status and CNS tissue source. Violin plots shown, each point represents a unique sample, and the score indicates number of unique KCNQ2∆E5 reads. P-values are the result of unpaired one-sided Wilcoxon Rank Sum tests. (b) Boxplots displaying abundance of KCNQ2, STMN2 and UNC13A in CNS regions. Points reflect gene expression from individual patient CNS samples from Target ALS/NYGC. Boxes show the interquartile range of gene expression in TPMs, whiskers reflect those beyond the interquartile range. Number of unique samples indicated within the panel. (c) Relative abundance of TDP-43 targets KCNQ2, STMN2 and UNC13A in human cortex and spinal cord using the same datasets employed for splicing analyses in Fig. 2a-e. Data shown as violin plots with underlying gene expression values from postmortem samples (datapoints). P-values are the result of unpaired, two-sided t-tests. (d) Proportion of regional CNS tissue samples with aberrant splicing events. Left: KCNQ2∆E5; Middle: cryptic truncation of STMN2; Right: cryptic exon inclusion in UNC13A. Numbers of samples with and without detection of events are included (detected: not detected). (e) Expression of KCNQ2, STMN2 and UNC13A in different cell types in the human cortex. Data from Schirmer et al.95 and Velmeshev et al.96. (f) Related to Fig. 2f-i. Correlation between KCNQ2∆E5 abundance by qRT-PCR and disease duration. P-values are the result of linear regression models adjusted for age at death, sex, and RIN. For additional statistics see Supplementary Table 2.
