Table 1.
Effects of DM1 on the regulation of alternative splicing in TA muscle. For each splice event, the fraction of splice products that included or skipped the alternative exon(s) was compared for eight healthy controls and 33 DM1 subjects with ADF weakness (MRC score of 4+ or below, “weak DM1”). Splice events are listed in descending order of effect size (percentage splicing shift) in the weak DM1 vs. healthy subjects. The correlation of splicing outcome with weakness is calculated for all DM1 subjects (weak or not weak, n = 50). Splice events that show early transition (misregulated splicing in TA with normal strength) are underlined. Downward arrows indicate that inclusion of the exon is reduced in DM1, upward arrows indicates that exon inclusion is increased. Splicing shift is the absolute difference of exon inclusion (or exclusion) in DM1 vs. controls, as calculated from signal intensity of RT-PCR products: exon inclusion (or exclusion) product ÷ sum of all products × 100%.
| Splice event | % splicing shift in weak DM1 vs. healthy, direction of shift (P value) | Correlation of splicing with weakness (P value) | Function of gene product (effect of splicing change) |
|---|---|---|---|
| SOS1 exon 25 | 82.6 ↓ (1.E-25) | 0.57 (1.5E-05) | receptor signaling (↓ signaling) |
| ATP2A1 exon 22 | 78.3 ↓ (3.E-09) | 0.65 (4.0E-07) | Ca++ reuptake |
| ALPK3 exon 2 | 71.9 ↑ (4.E-16) | 0.64 (6.6E-07) | signaling, myogenesis |
| NFIX exon 7 | 68.1 ↑ (1.E-15) | 0.68 (7.5E-08) | transcription factor, myogenesis |
| INSR exon 11 | 66.2 ↓ (6.E-26) | 0.44 (1.5E-03) | insulin signaling (Δ signaling) |
| CAPZB exon 8 | 66.1 ↓ (6.E-18) | 0.65 (2.5E-07) | assembly of actin filaments |
| ARFGAP2 exon 6 | 65.2 ↓ (5.E-25) | 0.36 (1.1E-02) | vesicle trafficking |
| PDLIM3 exon 5 | 65.0 ↓ (3.E-12) | 0.70 (1.5E-08) | Z disc |
| CACNA1S exon 29 | 64.3 ↓ (3.E-16) | 0.67 (1.3E-07) | excitation contraction coupling (↑ Ca++ entry) |
| CAMK2B exon 13 | 62.9 ↓ (3.E-31) | 0.44 (1.4E-03) | Signaling |
| VPS39 exon 3 | 62.4 ↓ (1.E-14) | 0.58 (8.3E-06) | vesicle trafficking, TGFbeta signaling |
| CLCN1 exon 7a | 58.5 ↑ (2.E-25) | 0.52 (1.3E-04) | chloride channel (loss of ion conductance) |
| LDB3 exon 11 | 53.0 ↑ (3.E-05) | 0.58 (1.1E-05) | Z disc |
| GFPT1 exon 9 | 50.6 ↓ (9.E-12) | 0.66 (2.3E-07) | protein glycosylation (↓ feedback inhibition) |
| DTNA (DB2) exons 11a, 12 | 47.5 ↑ (4.E-12) | 0.71 (1.0E-08) | membrane integrity, signaling (altered signaling) |
| IMPDH2 exon 9b | 44.3 ↓ (1.E-24) | 0.57 (1.5E-05) | nucleotide biosynthesis |
| MBNL1 exon 7 | 42.8 ↑ (2.E-09) | 0.68 (6.7E-08) | alternative splicing (↑ nuclear localization) |
| NRAP exon 12 | 42.0 ↓ (1.E-10) | 0.46 (7.5E-04) | myofibril assembly |
| ANK2 exon 21 | 41.6 ↓ (3.E-08) | 0.70 (1.2E-08) | membrane targeting |
| OPA1 exon 4b | 40.9 ↓ (3.E-25) | 0.60 (3.6E-06) | mitochondrial dynamics (↑ proteolytic cleavage of OPA1 protein) |
| RYR1 exon 70 | 38.4 ↓ (8.E-19) | 0.45 (9.1E-040) | Ca++ release (↓ open probability) |
| COPZ2 exon 9b | 33.6 ↑ (2.E-07) | 0.33 (2.0E-02) | vesicle trafficking |
| KIF13A exon 32 | 33.5 ↓ (7.E-06) | 0.64 (4.8E-07) | positioning of endosomes |
| TTN exon Mex5 | 31.5 ↑ (8.E-30) | 0.50 (2.1E-04) | cytoskeletal protein |
| PHKA1 exon 28 | 28.8 ↓ (4.E-08) | 0.63 (9.0E-07) | muscle glycogenesis |
| FHOD1 exon 11a | 25.8 ↓ (2.E-09) | 0.39 (5.5E-03) | actin organization |
| MBNL2 exon 7 | 24.8 ↑ (8.E-09) | 0.55 (3.2E-05) | alternative splicing |
| DTNA (DB1) exons 11a, 12 | 23.8 ↑ (3.E-07) | 0.64 (4.9E-07) | membrane integrity, signaling (Δ signaling) |
| DMD exon 78 | 18.0 ↓ (3.E-06) | 0.71 (9.6E-09) | membrane integrity |
| PHKA1 exon 19 | 17.6 ↑ (3.E-05) | 0.68 (5.1E-08) | muscle glycogenesis |
| MLF1 exon 3 | 15.6 ↓ (1.E-04) | 0.58 (1.1E-05) | oncoprotein |
| ABLIM2 exon 12 | 14.6 ↑ (2.E-07) | 0.65 (3.0E-07) | Z disc |
| UBE2D3 exon 10 | 14.2 ↓ (1.E-25) | 0.55 (2.9E-05) | Ubiquitination |
| BIN1 exon 11 | 14.0 ↓ (5.E-04) | 0.72 (4.5E-09) | T-tubule formation (↓ formation of T tubules) |
| LDB3 exon 5 | 13.6 ↑ (3.E-17) | 0.49 (2.6E-04) | Z disc |
| DMD exon 71 | 13.3 ↓ (3.E-04) | 0.62 (1.9E-06) | membrane integrity |
| TBC1D15 exon 10 | 13.1 ↓ (7.E-18) | 0.42 (2.6E-03) | intracellular trafficking |
| USP25 exons 19a,19b | 12.5 ↓ (1.E-05) | 0.45 (1.1E-03) | deubiquitination (↑ proteolysis of muscle proteins) |
| TXNL4A exon 4 | 12.5 ↓ (1.E-09) | 0.38 (6.9E-03) | PQBP1 binding protein |
| VEGFA exons 6a, 6b | 7.3 ↓ (2.E-15) | 0.45 (1.0E-03) | angiogenesis (altered diffusibility) |
| CAPN3 exon 16 | 6.4 ↓ (3.E-06) | 0.64 (5.0E-07) | intracellular protease (↓ protease activity) |
| ATP2A2 intron 19 | 3.8 ↓ (1.E-08) | 0.45 (1.1E-03) | Ca++ reuptake |