VKORC1 mutants at the proper redox state exhibit WR, reflecting their increased clinical doses, and patients carrying certain mutations are potentially untreatable by warfarin
| . | WR (IC50 mutant/WT ± SEM) . | Cases # . | Typical dose (mg/d)25,38 . | Stable INR (2-3) . | Uninhibited activity . | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| GSH . | DTT . | Cell . | |||||||||
| This study . | This study . | Lattard25 . | This study . | Li32 . | Tie39 . | Oldenburg40 . | |||||
| WT | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.7 | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.1 | 1.0 ± 0.2 | 4∗ | Yes | ||
| A26P∗ | 55.3 ± 9.5 | 10.1 ± 1.5 | 11.2 ± 6.4 | 50.8 ± 8.8 | 60.4 ± 13.2 | 72.0 ± 9.4 | 49.6 ± 7.2 | 1 | 20 | No | 41% |
| A26T | 1.3 ± 0.7 | 1.9 ± 0.4 | 3.0 ± 0.5 | 1 | 6 | No | |||||
| L27V | 1.1 ± 0.7 | 1.6 ± 0.3 | 1.4 ± 0.2 | 2.5 ± 0.5 | 1 | 7 | Yes | ||||
| H28W | 0.4 ± 0.3 | 2.5 ± 0.6 | 1.3 ± 0.2 | 2.9 ± 0.5 | 1 | 10 P† | Yes | ||||
| V29L | 9.4 ± 5.6 | 1.1 ± 0.2 | Low exp. | 15.9 ± 2.9 | 20.7 ± 3.3 | 19.2 ± 4.2 | 5.5 ± 0.8 | 3 | 14 | Yes | |
| A34P | 14.1 ± 10.1 | 1.9 ± 0.4 | 22.6 ± 7.7 | 27.2 ± 2.6 | 19.4 ± 4.4 | 1 | 27 | Yes | |||
| D36G | 0.4 ± 0.3 | 2.5 ± 0.4 | 2.1 ± 0.5 | 3.2 ± 0.5 | 1 | 20 | Yes | ||||
| D36Y | 1.1 ± 0.7 | 1.3 ± 0.2 | 3.8 ± 1.0 | 164 | 8-20 | Yes | |||||
| A41S | 1.1 ± 0.5 | 1.3 ± 0.3 | 1.9 ± 0.3 | 1 | 16 | Yes | |||||
| V45A | 0.7 ± 0.3 | 2.2 ± 0.5 | 2.6 ± 0.6 | 6.2 ± 0.9 | 1 | 45 | No | ||||
| S52L | Low act. | 23.3 ± 4.5 | 7.4 ± 1.1 | 1 | 9 P | No | |||||
| S52W | Low act. | 4.5 ± 0.9 | 6.6 ± 1.2 | 5.7 ± 1.2 | 1 | 10 P | Yes | ||||
| V54L | 8.2 ± 2.7 | 8.2 ± 1.6 | 4.8 ± 2.4 | 9.7 ± 2.0 | 11.8 ± 2.2 | 8.5 ± 1.6 | 4.5 ± 0.7 | 3 | 5-37 | Yes | |
| S56F | 0.6 ± 0.6 | 2.2 ± 0.5 | 1.6 ± 0.3 | 6.8 ± 1.1 | 1 | 15 P | No | ||||
| R58G | 0.9 ± 0.5 | 3.5 ± 0.8 | 6.0 ± 0.8 | 3.4 ± 0.6 | 4 | 34 | Yes | ||||
| W59R∗ | 115.4 ± 31.5 | 3.7 ± 0.7 | Low act. | 93.8 ± 26.3 | 84.9 ± 14.3 | 98.0 ± 12.8 | 17.5 ± 2.6 | 3 | 9 P | No | 27% |
| W59C | 0.7 ± 0.4 | 19.6 ± 3.0 | 7.6 ± 1.2 | 1 | 11 P | No | |||||
| W59L∗ | Low act. | 84.5 ± 14.1 | 75.2 ± 11.0 | 1 | 15 P | No | |||||
| V66G | Low act. | 3.9 ± 0.7 | 2.8 ± 0.5 | 1 | 8 P | Yes | |||||
| V66M | Low act. | 3.3 ± 0.6 | 1.3 ± 0.2 | 5.4 ± 0.8 | 15 | 30 | Yes | ||||
| H68T | 3.8 ± 1.9 | 1.0 ± 0.2 | 5.1 ± 0.8 | 1 | |||||||
| G71A | Low act. | 1.6 ± 0.2 | 1 | 6 P | No | ||||||
| N77S | Low act. | 6.0 ± 1.2 | 5.3 ± 1.0 | 1 | 9 P | No | |||||
| N77Y | 5.9 ± 2.0 | 2.1 ± 1.0 | Low act. | 2.5 ± 0.9 | 9.4 ± 1.3 | 3.9 ± 0.6 | 3.9 ± 0.6 | 1 | 25 | Yes | |
| I123N | 6.5 ± 1.9 | 2.2 ± 0.4 | 2.4 ± 1.3 | 8.8 ± 2.2 | 9.0 ± 1.0 | 3.4 ± 0.5 | 8.5 ± 1.2 | 1 | 21 P | No | |
| L128R | 36.5 ± 7.7 | 1.1 ± 0.2 | Low act. | 36.2 ± 11.8 | 39.7 ± 8.3 | 84.5 ± 14.6 | 49.6 ± 7.2 | 9 | 39-49 | No | 22% |
| Y139H | 7.1 ± 3.3 | 4.4 ± 1.0 | 3.6 ± 2.0 | 8.9 ± 1.7 | 6.6 ± 1.0 | 4.7 ± 0.6 | 4.6 ± 0.7 | 1 | 9 P | No | |
| . | WR (IC50 mutant/WT ± SEM) . | Cases # . | Typical dose (mg/d)25,38 . | Stable INR (2-3) . | Uninhibited activity . | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| GSH . | DTT . | Cell . | |||||||||
| This study . | This study . | Lattard25 . | This study . | Li32 . | Tie39 . | Oldenburg40 . | |||||
| WT | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.7 | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.1 | 1.0 ± 0.2 | 4∗ | Yes | ||
| A26P∗ | 55.3 ± 9.5 | 10.1 ± 1.5 | 11.2 ± 6.4 | 50.8 ± 8.8 | 60.4 ± 13.2 | 72.0 ± 9.4 | 49.6 ± 7.2 | 1 | 20 | No | 41% |
| A26T | 1.3 ± 0.7 | 1.9 ± 0.4 | 3.0 ± 0.5 | 1 | 6 | No | |||||
| L27V | 1.1 ± 0.7 | 1.6 ± 0.3 | 1.4 ± 0.2 | 2.5 ± 0.5 | 1 | 7 | Yes | ||||
| H28W | 0.4 ± 0.3 | 2.5 ± 0.6 | 1.3 ± 0.2 | 2.9 ± 0.5 | 1 | 10 P† | Yes | ||||
| V29L | 9.4 ± 5.6 | 1.1 ± 0.2 | Low exp. | 15.9 ± 2.9 | 20.7 ± 3.3 | 19.2 ± 4.2 | 5.5 ± 0.8 | 3 | 14 | Yes | |
| A34P | 14.1 ± 10.1 | 1.9 ± 0.4 | 22.6 ± 7.7 | 27.2 ± 2.6 | 19.4 ± 4.4 | 1 | 27 | Yes | |||
| D36G | 0.4 ± 0.3 | 2.5 ± 0.4 | 2.1 ± 0.5 | 3.2 ± 0.5 | 1 | 20 | Yes | ||||
| D36Y | 1.1 ± 0.7 | 1.3 ± 0.2 | 3.8 ± 1.0 | 164 | 8-20 | Yes | |||||
| A41S | 1.1 ± 0.5 | 1.3 ± 0.3 | 1.9 ± 0.3 | 1 | 16 | Yes | |||||
| V45A | 0.7 ± 0.3 | 2.2 ± 0.5 | 2.6 ± 0.6 | 6.2 ± 0.9 | 1 | 45 | No | ||||
| S52L | Low act. | 23.3 ± 4.5 | 7.4 ± 1.1 | 1 | 9 P | No | |||||
| S52W | Low act. | 4.5 ± 0.9 | 6.6 ± 1.2 | 5.7 ± 1.2 | 1 | 10 P | Yes | ||||
| V54L | 8.2 ± 2.7 | 8.2 ± 1.6 | 4.8 ± 2.4 | 9.7 ± 2.0 | 11.8 ± 2.2 | 8.5 ± 1.6 | 4.5 ± 0.7 | 3 | 5-37 | Yes | |
| S56F | 0.6 ± 0.6 | 2.2 ± 0.5 | 1.6 ± 0.3 | 6.8 ± 1.1 | 1 | 15 P | No | ||||
| R58G | 0.9 ± 0.5 | 3.5 ± 0.8 | 6.0 ± 0.8 | 3.4 ± 0.6 | 4 | 34 | Yes | ||||
| W59R∗ | 115.4 ± 31.5 | 3.7 ± 0.7 | Low act. | 93.8 ± 26.3 | 84.9 ± 14.3 | 98.0 ± 12.8 | 17.5 ± 2.6 | 3 | 9 P | No | 27% |
| W59C | 0.7 ± 0.4 | 19.6 ± 3.0 | 7.6 ± 1.2 | 1 | 11 P | No | |||||
| W59L∗ | Low act. | 84.5 ± 14.1 | 75.2 ± 11.0 | 1 | 15 P | No | |||||
| V66G | Low act. | 3.9 ± 0.7 | 2.8 ± 0.5 | 1 | 8 P | Yes | |||||
| V66M | Low act. | 3.3 ± 0.6 | 1.3 ± 0.2 | 5.4 ± 0.8 | 15 | 30 | Yes | ||||
| H68T | 3.8 ± 1.9 | 1.0 ± 0.2 | 5.1 ± 0.8 | 1 | |||||||
| G71A | Low act. | 1.6 ± 0.2 | 1 | 6 P | No | ||||||
| N77S | Low act. | 6.0 ± 1.2 | 5.3 ± 1.0 | 1 | 9 P | No | |||||
| N77Y | 5.9 ± 2.0 | 2.1 ± 1.0 | Low act. | 2.5 ± 0.9 | 9.4 ± 1.3 | 3.9 ± 0.6 | 3.9 ± 0.6 | 1 | 25 | Yes | |
| I123N | 6.5 ± 1.9 | 2.2 ± 0.4 | 2.4 ± 1.3 | 8.8 ± 2.2 | 9.0 ± 1.0 | 3.4 ± 0.5 | 8.5 ± 1.2 | 1 | 21 P | No | |
| L128R | 36.5 ± 7.7 | 1.1 ± 0.2 | Low act. | 36.2 ± 11.8 | 39.7 ± 8.3 | 84.5 ± 14.6 | 49.6 ± 7.2 | 9 | 39-49 | No | 22% |
| Y139H | 7.1 ± 3.3 | 4.4 ± 1.0 | 3.6 ± 2.0 | 8.9 ± 1.7 | 6.6 ± 1.0 | 4.7 ± 0.6 | 4.6 ± 0.7 | 1 | 9 P | No | |