Table 1.
Mutations identified in KCNJ10/Kir4.1.
| Mutation | CADD score | Associated phenotypes | Typical/Atypical/ASD | Function (expressed alone) | Reference | ||||
|---|---|---|---|---|---|---|---|---|---|
| E | A | S | T | WM | |||||
| R18Q | 22.4 | Y | Y | N | N | N | ASD | Gain of function | Sicca et al., 2011, 2016 |
| T57I | 25.8 | Y | Y | Y | Y | N | T | Complete LOF | Scholl et al., 2012 |
| I60T | 24.9 | Y | Y | ND | N | Y | A | Not determined | Al Dhaibani et al., 2018 |
| I60M | 22.5 | N | Y | Y | N | N | A | Not determined | Nicita et al., 2018 |
| R65C | 29.1 | Y | Y | Y | Y | N | T | Not determined | Papavasiliou et al., 2017 |
| R65C | 29.1 | Y | Y | Y | Y | Y | T | Not determined | Celmina et al., 2019 |
| R65C | 29.1 | Y | Y | Y | Y | ND | T | 82% reduction in currents | Freudenthal et al., 2011 |
| R65P | 28.5 | Y | ND | ND | ND | ND | T | Not determined | Thompson et al., 2011 |
| R65P | 28.5 | Y | Y | Y | Y | N | T | 75% reduction in currents | Bockenhauer et al., 2009; Williams et al., 2010 |
| R65P | 28.5 | Y | Y | Y | Y | ND | T | >80% reduction in currents | Scholl et al., 2009; Reichold et al., 2010; Williams et al., 2010 |
| L68P | 26.0 | Y | Y | ? | ? | ? | ? | Not determined | Lemke et al., 2012 |
| F75C | 27.7 | Y | Y | Y | Y | ND | T | Complete loss of function | Parrock et al., 2013 |
| F75L | 23.6 | Y | Y | Y | Y | ND | T | >90% reduction in currents | Freudenthal et al., 2011 |
| G77R | 25.2 | Y | Y | Y | Y | ND | T | >90% reduction in currents | Bockenhauer et al., 2009; Reichold et al., 2010; Williams et al., 2010 |
| G83V | 26.4 | ? | ? | ? | ? | ? | ? | Complete loss of function | Mendez-Gonzalez et al., 2016 |
| V84M | 24.9 | Y | N | N | N | N | ASD | Gain of function | Sicca et al., 2011 |
| V91Gfs*197 | Y | Y | Y | Y | ND | T | Complete loss of function | Parrock et al., 2013 | |
| F119Gfs*25 | Y | Y | Y | Y | N | T | Not determined | Papavasiliou et al., 2017 | |
| I129V | 24.6 | Y | Y | ? | ? | ? | ? | Not determined | Lemke et al., 2012 |
| C140R | 26.7 | Y | Y | Y | Y | ND | T | Complete loss of function | Scholl et al., 2009; Williams et al., 2010 |
| G163D (1) | 26.8 | N | Y | Y | N | N | A | Complete loss of function | Morin et al., 2020 |
| T164I | 23.6 | Y | Y | Y | Y | Y | T | Complete loss of function | Scholl et al., 2009; Williams et al., 2010 |
| L166Q | 27.2 | ? | ? | ? | ? | ? | ? | 50% reduction in currents | Mendez-Gonzalez et al., 2016 |
| A167V | 25.8 | N | N | N | Y | ND | A | 40% reduction in currents | Parrock et al., 2013; Suzumoto et al., 2021 |
| A167V (6) | 25.8 | Y | Y | Y | Y | ND | T | ~50% with R297C | Scholl et al., 2009; Williams et al., 2010 |
| R171Q (1) | 28.1 | N | Y | Y | N | N | A | 50% reduction in currents | Morin et al., 2020 |
| R175Q | 29.8 | Y | Y | Y | Y | ND | T | >90% reduction in currents | Reichold et al., 2010 |
| P194H (2) | 23.7 | N | N | Y | N | ND | A | 51% reduction in currents | Yang et al., 2009 |
| R199* | Y | Y | Y | Y | ND | ? | Complete loss of function | Scholl et al., 2009; Reichold et al., 2010; Williams et al., 2010; Thompson et al., 2011 | |
| A201T (3) | 27.4 | Y | Y | N | N | N | A | Almost complete loss of function | Zhang et al., 2019 |
| R204H | 29.2 | Y | Y | Y | Y | N | T | Not determined | Kara et al., 2013 |
| I209T (3) | 25.9 | Y | Y | N | N | N | A | 37% reduction in currents | Zhang et al., 2019 |
| Q212R | 26.0 | ? | ? | ? | ? | ? | ? | Currents similar to WT | Mendez-Gonzalez et al., 2016 |
| L218F (4) | 27.3 | Y | Y | N | N | N | A | 60% reduction in currents | Hasan et al., 2017 |
| N232Qfs*14 | Y | Y | Y | Y | Y | T | Not determined | Severino et al., 2018; Suzumoto et al., 2021 | |
| V259* | Y | Y | Y | Y | ND | T | Complete loss of function | Freudenthal et al., 2011 | |
| G275Vfs*7 | Y | Y | N | Y | Y | A | Predicted to be deleterious | Severino et al., 2018; Suzumoto et al., 2021 | |
| T290A | 25.8 | Y | Y | Y | N | N | A | 60% reduced currents (LCL) | Nadella et al., 2019 |
| R297C | 32 | Y | Y | Y | Y | ND | T | >90% reduction in currents | Freudenthal et al., 2011; Thompson et al., 2011 |
| R297C | 32 | Y | Y | Y | Y | ND | T | Complete loss of function | Scholl et al., 2009; Williams et al., 2010 |
| R348C (2) | 22.7 | N | N | Y | N | ND | ? | 44% reduction in currents | Yang et al., 2009 |
| R348H | 16.5 | Y | N | N | N | ND | ASD | Gain of function | Sicca et al., 2016 |
| >25% Residual function | |||||||||
| <25% Residual function | |||||||||
| Atypical features | |||||||||
| Gain of function | |||||||||
| Function unknown | |||||||||
Table 1 summarizes the consequences of KCNJ10 mutations. CADD score according to https://cadd.gs.washington.edu/snv (Rentzsch et al., 2019). Associated phenotypes refer to epilepsy (E), ataxia (A), sensorineural deafness (S), tubulopathy, hypokalemia and alkalosis (T), white matter abnormalities (WM), and autism spectrum disorder (ASD). Yes (Y); No (N); Not determined (ND). * indicates a “stop codon”. Color code is shown for functional effects when expressed as homomeric Kir4.1. Note that pink coloration was given to “atypical” (=A) mutations which lead to partial EAST syndrome, that is, lack some of its characteristic features, as opposed to “typical,” featuring all cardinal symptoms Epilepsy, Ataxia, Sensorineural hearing loss, and renal Tubulopathy. LCL: Kir4.1 T290A was examined in patient-derived lymphoblast cells. (1) Compound heterozygous state. (2) With mutations in Slc26A4. (3) Compound heterozygous state. (4) With mutation in KCNT1. (5) With mutations in Slc26A4.