Table 2 Splice‐site mutations discovered in this study and their consequences, as predicted by the splice‐site predictor.
| Location | cDNA position | Splice‐site score | Theoretical predictions at mRNA protein level | ||
|---|---|---|---|---|---|
| Normal | Mutant | ||||
| Putative splice‐site mutations found in patients with dominant inheritance pattern | |||||
| Intron 35 | 4120−1 G→C | 0.94 | LAS | Skip ex 36→IF | |
| Exon 48 (acceptor+1) | 4669G→C (G1557R) | 0.88 | 0.45 | a. NC | |
| b. Skip ex 48→IF | |||||
| Intron 69 | 5772+1 G→T | 0.96 | LDS | Skip ex 69→IF | |
| Exon 83 (acceptor+1) | 6619G→C (G2207R) | 0.95 | 0.69 | a. NC | |
| b. Skip ex 83→IF | |||||
| Intron 87 | 6900+1 G→T | 0.13* | LDS | Skip ex 87→IF | |
| Intron 87 | 6900+4 A→G | 0.13* | LDS | Skip ex 87→IF | |
| Exon 108 (donor−2) | 8045A→G (K2682R) | 0.91 | LDS | Skip ex 108→IF | |
| Putative splice‐site mutations found in patients with recessive inheritance pattern | |||||
| Exon 3 (donor−2) | 425A→G (K142R) | 0.84 | LDS | Skip ex 3→OF, PTC in ex 4 | |
| Intron 3 | 427−3 C→G | 0.83 | LAS | Skip ex 4→OF, PTC in ex 5 | |
| Intron 4 | 521−2 A→C | 0.52 | LAS | Skip ex 5→IF | |
| Intron 5 | 682+1 G→C | 0.90 | LDS | Skip ex 5→IF | |
| Intron 6 | 847−1 G→C | 0.34 | LAS | Skip ex 7→OF, PTC in ex 8 | |
| Intron 11 | 1507+1 G→C | 0.96 | LDS | Skip ex 11→IF | |
| Intron 12 | 1637−1 G→A | 0.97 | LAS | Novel CAS (0.90) 1 bp DS→OF, PTC in ex 14 | |
| Intron 20 | 2710+2 T→C | 0.62 | LDS | Skip ex 20→IF | |
| Intron 21 | 2858−1 G→A | 0.97 | LAS | a. Activation of CAS (score 0.97) 40 bp US→PTC in int 21 | |
| b. Novel CAS (score 0.69) 2 bp DS→OF, PTC in ex 22 | |||||
| c. Skip ex 22→IF | |||||
| Exon 31 (acceptor+1) | 3832del2 | 0.98 | 0.98 | PTC in ex 35 | |
| Exon 33 (donor−1) | 4011G→A | 0.99 | 0.58 | a. NC | |
| b. Skip ex 33→IF | |||||
| Intron 34 | 4048−1 G→A | 0.98 | LAS | a. Novel CAS (score 0.25) 101 bp US→OF, PTC in int 34 | |
| b. Novel CAS (score 0.20) 1 bp DS→OF, PTC in ex 36 | |||||
| c. Skip ex 35→IF | |||||
| Intron 35 | 4119+1 G→C | 1.00 | LDS | a. Novel CDS (score 0.92) 11 bp DS→OF, PTC in ex 36 | |
| b. Skip ex 36→IF | |||||
| Intron 42 | 4482+1 G→A | 1.00 | LDS | Skip ex 42→IF | |
| Intron 51 | 4899+1 G→T | 0.91 | LDS | a. Novel CDS (score 0.97) 32 bp DS→OF, PTC in ex 57 | |
| b. Skip ex 51→IF | |||||
| Exon 54 (donor−1) | 5052insGAAA | 0.99 | 0.95 | PTC in ex 55 | |
| Exon 69 (donor−2) | 5771A→C (Q1924P) | 0.96 | 0.78 | a. NC | |
| b. Skip ex 69→IF | |||||
| Exon 70 (donor−2) | 5819delC | 0.92 | 0.79 | PTC in ex 73 | |
| Exon 70 (donor−2) | 5819C→T (P1940L) | 0.92 | 0.80 | a. NC | |
| b. Skip ex 70→IF | |||||
| Intron 74 | 6216+5 G→T | 0.83 | LDS | Skip ex 74→IF | |
| Exon 79 (donor−1) | 6501G→A | 0.99 | 0.91 | a. Activation of CDS (score 0.96) 245 bp DS in int 79→PTC in int 79 | |
| b. NC | |||||
| c. Skip ex 79→IF | |||||
| Intron 79 | 6501+1G→C | 0.99 | LDS | Skip ex 79→IF | |
| Intron 81 | 6573+1 G→C | 0.99 | LDS | a. Activation of CDS (score 0.94) 25 bp DS→OF, PTC in ex 87 | |
| b. Skip ex 81→IF | |||||
| Intron 82 | 6619−2 A→T | 0.95 | LAS | Skip ex 83→IF | |
| Exon 84 (acceptor+3) | 6654C→G | 0.98 | 0.98 | NC | |
| Intron 85 | 6751−2 A→G | 0.99 | LAS | Skip ex 86→IF | |
| Exon 86 (acceptor+1) | 6751del2 | 0.99 | 0.97 | PTC in ex 87 | |
| Exon 86 (acceptor+2) | 6752G→C (G2251A) | 0.99 | 0.99 | NC | |
| Exon 92 (acceptor+1) | 7069G→A (G2357S) | 0.96 | 0.93 | a. NC | |
| b. Skip ex 92→IF | |||||
| Intron 92 | 7104+5 G→A | 1.00 | 0.75 | a. NC | |
| b. Skip ex 92→IF | |||||
| Exon 95 (donor−1) | 7344G→A | 0.98 | LDS | a. Novel CDS (score 0.76) 7 bp US→OF, PTC in ex 97 | |
| b. Skip ex 95→IF | |||||
| Intron 98 | 7485+2 T→G | 0.90 | LAS | Skip ex 98→IF | |
| Intron 105 | 7875+1 G→C | 0.96 | LDS | Skip ex 105→IF | |
| Intron 106 | 7929+5 A→C | 0.91 | 0.87 | a. NC | |
| b. Skip ex 106→IF | |||||
| Intron 106 | 7929+11del16 | 0.91 | 0.91 | a. Novel CDS (score 0.96) 10 bp DS→OF, PTC in ex 108 | |
| b. Skip ex 106→IF | |||||
| Intron 106 | 7930−1 G→A | 0.44 | LAS | Skip ex 107→IF | |
| Intron 110 | 8227−1 G→C | 0.73 | LAS | Skip ex 111→IF | |
| Intron 113 | 8407+5 G→C | 0.96 | LDS | Skip ex 113→OF, PTC in ex 117 | |
| Intron 117 | 8819−1 G→C | 0.87 | LAS | Skip ex 118 | |
bp, base pair; CAS, cryptic acceptor splice site; CDS, cryptic donor splice site; DS, downstream; ex, exon; IF, in‐frame translation; int, intron; LAS, loss of acceptor splice site; LDS, loss of donor splice site; NC, no change to splice site; OF, out‐of‐frame translation; PTC, premature termination codon; US, upstream.
Consequences of these mutations have not been analysed at the mRNA level.
*Estimated accuracy of prediction was adjusted due to failure to recognise wild‐type splice site by the splice‐site predictor. Minimum score was changed to 0.05, allowing for 98.3% of sites to be recognised with an 11.1% false‐positive rate.