Table 1.
Ability of ATP1A3 mutations to support cell survival in HEK-293.
| mutation | [ouab] μM |
survival/ growth |
phenotypes | age at onset |
recurrence | ref. for survival assay |
1st ref. for patients |
|
|---|---|---|---|---|---|---|---|---|
| α3 WTor | 0.5-10 | +++ | − | − | − | (1) | ||
| R463C | 3 | +++ | (VUS) | dystonia, tremor, parkinsonism | 60 y | 130 in gnomAD | this work | (2) |
| I274T | 10 | ++ | mild | RDP | 37 y | no, but I274N | (1) | |
| E277K“ | 10 | + | mild intermed. | RDP late AHC | 14-26 y 2.6 y | yes | (1) | (1,3) |
| G316S | 0.5 | +/− | mild | ataxia-RDP | 19 y | no | (4) | |
| G358V | 0.5 | − | severe | EIEE | 4 h | no | (5) | |
| I363N | 0.5 | − | severe | EIEE | 6 w | no | (5) | |
| D366H | 3 | − | mild | RDP | 16 y | no | this work | |
| C596R | 0.5 | − | severe | AHC | 3 w | no | this work | (6) |
| T613M | 10 | + | mild | RDP | 8-28 y | yes | (1) | |
| S729Y* | 0.5 | +++ | (VUS) | − | no | this work | ||
| D742Y“ | 3 | − | (severe) severe | ataxia-RDP paroxysmal | 1 y 6 w | yes | this work | (7) |
| D743H* | 3 | − | mild | RDP | no | this work | ||
| I758S | 10 | + | mild | RDP | 14-45 y | no, but I758F | (1) | |
| F780L | 10 | + | mild | RDP | 16-35 y | no | (1) | |
| D801Y“ | 10 | +/− | mild severe | RDP AHC | 12-23 y 14 mo | yes | (1) | (1,6) |
| E815K | 3 | − | severe | AHC | 1 w-18 m | yes | this work | (8) |
| D923N““ | 3 | + | severe intermed. mild | AHC late AHC RDP | 2 m,8 m 10 @ 2-4y 2 @ 20 y | yes | this work | (9-11) |
| L924P | 3 | ++ | severe | EIEE | 3 d | no | this work | |
| G947R | 0.5 | +/− | severe | AHC | 1 w-18 m | yes | this work | (8) |
Survival was scored as follows. No survival, −. Survival of some cells but no cell division, +/−. Slow, intermediate, and normal growth in ouabain, +, ++, and +++ respectively. The clinical syndrome most closely matching the phenotype seen is given, and phenotypes were categorized as severe (onset under 18 months of age), intermediate (2-4 years of age here) and mild (onset from 8 years to middle age). The use of different concentrations of ouabain depended on the investigator; all concentrations were sufficient, and some were in excess. Note that while four mutations presenting with severe phenotypes showed no survival in ouabain, another two mutations presenting with mild phenotypes also did not survive (boldface). L924P is a mutation with severe phenotype (fatal in this case) yet cells survived. Independent recurrence of each mutation is stated; one family is one occurrence. VUS: variant of unknown significance.
These two variants occurred in the same patient. WTOR, ouabain-resistant wild type ATP1A3. References: 1) (de Carvalho Aguiar et al., 2004), 2) (Yang et al., 2014), 3) (Boelman et al., 2014), 4) (Sweadner et al., 2016), 5) (Paciorkowski et al., 2015), 6) (Viollet et al., 2015), 7) (Marzin et al., 2018), 8) (Heinzen et al., 2012), 9) (Roubergue et al., 2013), 10) (Anselm et al., 2009), 11) (Zanotti-Fregonara et al., 2008)