Figure 5.

Human TARDBP locus organization. Human TARDBP locus (black track; NCBI Gene ID: 23435), encoding full-length TDP-43 (FL) protein, is localized on chromosome 1p36.22 upstream of the MASP2 gene locus and counts up to 10 exons (obligatory and alternative exons). The blue tracks report the reference transcript coding for TDP-43 FL (NM_007375.4), as well as other predicted alternative transcripts isoforms (GENCODE. Version 42lift37 (Ensembl 108), ENST00000639083.1, ENST00000629725.2, ENST00000240185.8, ENST00000315091.7, ENST00000649624.1, ENST00000616545.4, and ENST00000621790.4,). NM_007375.4 is composed of six exons, flanked by a 5′ and a 3′ UTR. The 3′UTR embedded in exon 6 also contains two cryptic introns, intron 6* holding multiple alternative splicing sites and intron 7 (yellow frames, with splicing highlighted with blue dashed lines), as well as alternative polyadenylation signals (PAS) that have a fundamental importance for TDP-43 production control. The bottom dark green track shows the conservation within 100 vertebrates (“100 Vertebrates Conservation by PhastCons”). On the top of the TARDBP locus UCSC genome browser, tracks are reported. CpG score (red bars) shows different degrees of CpG methylation along the locus as found in the human cortex. H3K4me3 histone modification (green bars), the enrichment of which marks active promoter regions, is found upstream of exon 1 (TSS) down to exon 2. Common SNP (black and blue bars; from update V155) are found mainly within introns. OMIM variants (in green bars) are mainly in the exon 6, containing both the DNA and RNA signals for auto-regulation, and the region coding the C-term of the TDP-45 protein. All tracks are from the UCSC Genome Browser on Human (GRCh37/hg19).