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. Author manuscript; available in PMC: 2021 Jan 1.
Published in final edited form as: Hum Mutat. 2019 Oct 26;41(1):316–331. doi: 10.1002/humu.23930

Table 1.

Summaries of HCO3−/Cl− and l−/Cl− antiport assays and qualitative assessment of the fluorescence images of stable cell lines expressing the pendrin constructs generated in this study.

     ╲      Transport activity [mean ± SD (n)] Dox-dependence Protein expression
Dox: 0.1 μg/mL Dox: 0.3 μg/mL Dox: 1 μg/mL Dox: 3 μg/mL Dox: 10 μg/mL Transport activity/ log10 [Dox] (slope ± SE) Comparison to WT (F-test) At the cell membrane? Intracellular puncta?
WT HCO3−/Cl− 0.50 ± 0.21 (14) 0.92 ± 0.30 (16) 1.40 ± 0.28 (16) 1.86 ± 0.41 (16) 2.18 ± 0.41 (14) 0.861 ± 0.055 not applicable Yes Yes
[nM/sec] p = 0.0080 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.035 ± 0.010 (10) 0.083 ± 0.017 (10) 0.127 ± 0.018 (10) 0.157 ± 0.038 (10) 0.184 ± 0.038 (10) 0.074 ± 0.005 not applicable
[mM/sec] p = 0.18 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
N-terminal domain (NTD) Exon 2 P.S28G
(c.82A>G)		 HCO3−/Cl− 0.50 ± 0.12 (3) 0.67 ± 0.17 (3) 0.98 ± 0.29 (3) 0.90 ± 0.22 (3) 1.02 ± 0.11 (3) 0.251 ± 0.070 Function impaired Yes Yes
[nM/sec] p = 0.0016 p = 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0034 p < 0.0001
l−/Cl− 0.052 ± 0.008 (3) 0.104 ± 0.035 (3) 0.097 ± 0.033 (3) 0.116 ± 0.043 (3) 0.131 ± 0.039 (3) 0.034 ± 0.012 Function impaired
[mM/sec] p = 0.26 p = 0.0002 p = 0.0005 p < 0.0001 p < 0.0001 p = 0.0129 p = 0.0011
P.S49R
(c.147C>G)		 HCO3−/Cl− 0.90 ± 0.24 (3) 1.40 ± 0.08 (3) 2.09 ± 0.30 (3) 2.23 ± 0.09 (3) 2.73 ± 0.61 (3) 0.896 ± 0.113 WT-like Yes Yes
[nM/sec] p = 0.0008 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.78
l−/Cl− 0.078 ± 0.032 (3) 0.106 ± 0.027 (3) 0.148 ± 0.022 (3) 0.215 ± 0.035 (3) 0.178 ± 0.023 (3) 0.062 ± 0.013 WT-like
[mM/sec] p = 0.0003 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0003 p = 0.29
Exon 3 p.P76S
(c.226C>T)		 HCO3−/Cl− 0.36 ± 0.08 (3) 0.51 ± 0.16 (3) 0.80 ± 0.10 (3) 0.80 ± 0.22 (3) 0.87 ± 0.08 (3) 0.263 ± 0.052 Function impaired Yes No
[nM/sec] p = 0.0022 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0002 p < 0.0001
l−/Cl− 0.038 ± 0.004 (3) 0.059 ± 0.012 (3) 0.070 ± 0.006 (3) 0.074 ± 0.013 (3) 0.068 ± 0.013 (3) 0.015 ± 0.004 Function impaired
[mM/sec] p = 0.0036 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0052 p < 0.0001
Transmembrane domain (TMD) p.S90L
(c.269C>T)		 HCO3−/Cl− 0.042 ± 0.008 (3) 0.030 ± 0.003 (3) 0.057 ± 0.020 (3) 0.057 ± 0.022 (3) 0.031 ± 0.032 (3) 0.001 ± 0.008 Function impaired No No
[nM/sec] p = 0.77 p = 0.65 p = 0.22 p = 0.23 p = 0.68 p = 0.91 p < 0.0001
l−/Cl− 0.032 ± 0.004 (3) 0.027 ± 0.008 (3) 0.020 ± 0.004 (3) 0.020 ± 0.002 (3) 0.019 ± 0.005 (3) slope < 0 Function impaired
[mM/sec] p = 0.0048 p = 0.057 p = 0.88 p = 0.72 p = 0.56 ns* p < 0.0001
p.T99R
(c.296C>G)		 HCO3−/Cl− 0.071 ± 0.023 (3) 0.055 ± 0.031 (3) 0.059 ± 0.030 (3) 0.057 ± 0.005 (3) 0.059 ± 0.044 (3) slope < 0 Function impaired No No
[nM/sec] p = 0.12 p = 0.40 p = 0.30 p = 0.36 p = 0.31 p = 0.65 p < 0.0001
l−/Cl− 0.023 ± 0.005 (3) 0.017 ± 0.007 (3) 0.015 ± 0.006 (3) 0.011 ± 0.002 (3) 0.013 ± 0.002 (3) slope < 0 Function impaired
[mM/sec] p = 0.44 p = 0.34 p = 0.14 < control < control ns* p < 0.0001
Exon 4 p.L117F
(c.349C>T)		 HCO3−/Cl− 0.68 ± 0.34 (8) 1.16 ± 0.33 (9) 1.63 ± 0.53 (9) 2.07 ± 0.54 (9) 2.28 ± 0.34 (8) 0.822 ± 0.094 WT-like Yes Yes
[nM/sec] p = 0.0087 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.78
l−/Cl− 0.048 ± 0.016 (5) 0.078 ± 0.008 (5) 0.121 ± 0.019 (5) 0.165 ± 0.041 (5) 0.164 ± 0.015 (5) 0.064 ± 0.007 WT-like
[mM/sec] p = 0.0123 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.24
p.P123S
(c.367C>T)		 HCO3−/Cl− 0.045 ± 0.026 (3) 0.048 ± 0.053 (3) 0.062 ± 0.031 (3) 0.087 ± 0.021 (3) 0.088 ± 0.027 (3) 0.025 ± 0.011 Function impaired No No
[nM/sec] p = 0.75 p = 0.66 p = 0.29 p = 0.047 p = 0.042 p = 0.039 p < 0.0001
l−/Cl− 0.033 ± 0.012 (3) 0.027 ± 0.009 (3) 0.017 ± 0.003 (3) 0.016 ± 0.005 (3) 0.018 ± 0.002 (3) slope < 0 Function impaired
[mM/sec] p = 0.0061 p = 0.14 p = 0.49 p = 0.27 p = 0.55 ns* p < 0.0001
p.G131V
(c.392G>T)		 HCO3−/Cl− 0.012 ± 0.014 (3) 0.065 ± 0.010 (3) 0.093 ± 0.063 (3) 0.025 ± 0.029 (3) 0.039 ± 0.019 (3) 0.003 ± 0.015 Function impaired No No
[nM/sec] p = 0.29 p = 0.23 p = 0.025 p = 0.59 p = 0.92 p = 0.86 p < 0.0001
l−/Cl− 0.024 ± 0.012 (3) 0.020 ± 0.009 (3) 0.021 ± 0.008 (3) 0.019 ± 0.005 (3) 0.016 ± 0.008 (3) slope < 0 Function impaired
[mM/sec] p = 0.48 p = 0.90 p = 0.86 p = 0.74 p = 0.32 p = 0.24 p < 0.0001
p.S133T
(c.397T>A)		 HCO3−/Cl− 0.049 ± 0.005 (3) 0.042 ± 0.019 (3) 0.078 ± 0.064 (3) 0.077 ± 0.074 (3) 0.082 ± 0.059 (3) 0.020 ± 0.017 Function impaired No No
[nM/sec] p = 0.73 p = 0.90 p = 0.25 p = 0.25 p = 0.20 p = 0.25 p < 0.0001
l−/Cl− 0.026 ± 0.003 (3) 0.021 ± 0.007 (3) 0.019 ± 0.003 (3) 0.017 ± 0.003 (3) 0.015 ± 0.006 (3) slope < 0 Function impaired
[mM/sec] p = 0.098 p = 0.96 p = 0.67 p = 0.26 p = 0.11 ns* p < 0.0001
Exon 5 p-G139A
(c.416G>C)		 HCO3−/Cl− 0.053 ± 0.034 (3) 0.061 ± 0.037 (3) 0.051 ± 0.019 (3) 0.036 ± 0.003 (3) 0.056 ± 0.018 (3) slope < 0 Function impaired No No
[nM/sec] p = 0.40 p = 0.21 p = 0.46 p = 0.94 p = 0.33 p = 0.66 p < 0.0001
l−/Cl− 0.023 ± 0.006 (3) 0.020 ± 0.006 (3) 0.016 ± 0.009 (3) 0.015 ± 0.004 (3) 0.014 ± 0.006 (3) slope < 0 Function impaired
[mM/sec] p = 0.52 p = 0.85 p = 0.25 p = 0.17 p = 0.10 ns* p < 0.0001
p.M147T
(c.440T>C)		 HCO3−/Cl− 0.24 ± 0.10 (3) 0.21 ± 0.02 (3) 0.26 ± 0.08 (3) 0.25 ± 0.07 (3) 0.23 ± 0.08 (3) 0.005 ± 0.024 Function impaired No Yes
[nM/sec] p = 0.0008 p = 0.0021 p = 0.0003 p = 0.0005 p = 0.010 p = 0.84 p < 0.0001
l−/Cl− 0.025 ± 0.005 (3) 0.027 ± 0.001 (3) 0.031 ± 0.003 (3) 0.032 ± 0.003 (3) 0.028 ± 0.004 (3) 0.002 ± 0.001 Function impaired
[mM/sec] p = 0.11 p = 0.051 p = 0.002 p = 0.0009 p = 0.017 p = 0.13 p < 0.0001
p.M147V
(c.439A>G)		 HCO3−/Cl− 0.38 ± 0.20 (3) 0.41 ± 0.18 (4) 0.51 ± 0.24 (4) 0.51 ± 0.28 (4) 0.46 ± 0.20 (3) 0.055 ± 0.073 Function impaired No Yes
[nM/sec] p = 0.029 p = 0.012 p = 0.026 p = 0.0025 p = 0.0090 p = 0.46 p < 0.0001
l−/Cl− 0.027 ± 0.010 (3) 0.027 ± 0.003 (3) 0.031 ± 0.004 (3) 0.038 ± 0.011 (3) 0.035 ± 0.004 (3) 0.005 ± 0.002 Function impaired
[mM/sec] p = 0.11 p = 0.15 p = 0.023 p = 0.0005 p = 0.0022 p = 0.049 p < 0.0001
p.V163l
(c.487G>A)		 HCO3−/Cl− 0.61 ± 0.29 (4) 1.03 ± 0.36 (4) 1.52 ± 0.42 (4) 1.69 ± 0.51 (4) 2.54 ± 1.20 (4) 0.905 ± 0.191 WT-like Yes Yes
[nM/sec] p = 0.15 p = 0.019 p = 0.0011 p = 0.0004 p < 0.0001 p = 0.0002 p = 0.76
l−/Cl− 0.045 ± 0.017 (3) 0.076 ± 0.020 (3) 0.118 ± 0.016 (3) 0.167 ± 0.022 (3) 0.182 ± 0.064 (3) 0.073 ± 0.011 WT-like
[mM/sec] p = 0.13 p = 0.0018 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.88
p.V186F
(c.556G>T)		 HCO3−/Cl− 0.10 ± 0.02 (3) 0.11 ± 0.01 (3) 0.13 ± 0.06 (3) 0.087 ± 0.028 (3) 0.083 ± 0.033 (3) slope < 0 Function impaired No No
[nM/sec] p = 0.015 p = 0.0055 p = 0.0009 p = 0.049 p = 0.065 p = 0.35 p < 0.0001
l−/Cl− 0.016 ± 0.003 (3) 0.016 ± 0.005 (3) 0.017 ± 0.005 (3) 0.017 ± 0.002 (3) 0.017 ± 0.003 (3) 0.000 ± 0.001 Function impaired
[mM/sec] p = 0.20 p = 0.16 p = 0.28 p = 0.27 p = 0.23 p = 0.82 p < 0.0001
p.T193l
(c.578C>T)		 HCO3−/Cl− 0.023 ± 0.030 (4) 0.024 ± 0.016 (4) 0.023 ± 0.024 (4) 0.020 ± 0.025 (4) 0.046 ± 0.068 (4) 0.008 ± 0.011 Function impaired No No
[nM/sec] p = 0.57 p = 0.57 p = 0.55 p = 0.47 p = 0.71 p = 0.46 p < 0.0001
l−/Cl− 0.015 ± 0.007 (3) 0.015 ± 0.005 (3) 0.014 ± 0.006 (3) 0.011 ± 0.006 (3) 0.022 ± 0.007 (3) 0.002 ± 0.002 Function impaired
[mM/sec] p = 0.15 p = 0.15 p = 0.12 p = 0.032 p = 0.65 p = 0.32 p < 0.0001
Exon 6 p.Y214C
(c.641A>G)		 HCO3−/Cl− 0.47 ± 0.15 (3) 0.79 ± 0.03 (3) 0.89 ± 0.21 (3) 1.01 ± 0.09 (3) 1.04 ± 0.05 (3) 0.270 ± 0.049 Function impaired Yes Yes
[nM/sec] p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0001 p < 0.0001
l−/Cl− 0.055 ± 0.022 (3) 0.071 ± 0.019 (3) 0.118 ± 0.012 (3) 0.099 ± 0.006 (3) 0.109 ± 0.008 (3) 0.027 ± 0.007 Function impaired
[mM/sec] p = 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.023 p < 0.0001
p.V239D
(c.716T>A)		 HCO3−/Cl− 0.12 ± 0.03 (4) 0.19 ± 0.04 (4) 0.21 ± 0.05 (4) 0.17 ± 0.07 (4) 0.23 ± 0.10 (4) 0.042 ± 0.020 Function impaired Yes? No
[nM/sec] p = 0.053 p = 0.0011 p = 0.0004 p = 0.0032 p < 0.0001 p = 0.055 p < 0.0001
l−/Cl− 0.022 ± 0.006 (3) 0.024 ± 0.007 (3) 0.033 ± 0.007 (3) 0.038 ± 0.013 (3) 0.041 ± 0.015 (3) 0.010 ± 0.003 Function impaired
[mM/sec] p = 0.80 p = 0.50 p = 0.035 p = 0.0044 p = 0.0010 p = 0.0079 p < 0.0001
Exon 7 p.D266N
(c.796G>A)		 HCO3−/Cl− 0.82 ± 0.07 (3) 1.11 ± 0.08 (3) 2.15 ± 0.24 (3) 2.19 ± 0.58 (3) 2.57 ± 0.53 (3) 0.919 ± 0.141 WT-like Yes Yes
[nM/sec] p = 0.0043 p = 0.0004 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.67
l−/Cl− 0.042 ± 0.005 (3) 0.073 ± 0.005 (3) 0.129 ± 0.055 (3) 0.167 ± 0.020 (3) 0.176 ± 0.023 (3) 0.072 ± 0.010 WT-like
[mM/sec] p = 0.12 p = 0.0008 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.86
Exon 8 p.T307A
(c.919A>G)		 HCO3−/Cl− 0.73 ± 0.20 (4) 1.06 ± 0.32 (4) 1.70 ± 0.48 (4) 2.19 ± 0.45 (4) 2.43 ± 0.44 (4) 0.908 ± 0.117 WT-like Yes Yes
[nM/sec] p = 0.0085 p = 0.0003 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.69
l−/Cl− 0.051 ± 0.009 (3) 0.091 ± 0.006 (3) 0.122 ± 0.002 (3) 0.194 ± 0.013 (3) 0.212 ± 0.066 (3) 0.085 ± 0.011 WT-like
[mM/sec] p = 0.045 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.37
p.N324Y
(c.970A>T)		 HCO3−/Cl− 0.83 ± 0.08 (3) 1.30 ± 0.21 (3) 1.88 ± 0.11 (3) 2.33 ± 0.47 (3) 2.45 ± 0.91 (3) 0.856 ± 0.159 WT-like Yes Yes
[nM/sec] p = 0.017 p = 0.0007 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0001 p = 0.98
l−/Cl− 0.034 ± 0.004 (3) 0.085 ± 0.029 (3) 0.133 ± 0.009 (3) 0.166 ± 0.012 (3) 0.215 ± 0.040 (3) 0.089 ± 0.008 WT-like
[mM/sec] p = 0.22 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.19
p.G334V
(c.1001G>T)		 HCO3−/Cl− 0.67 ± 0.15 (3) 0.93 ± 0.18 (3) 1.19 ± 0.39 (3) 1.61 ± 0.28 (3) 1.61 ± 0.17 (3) 0.512 ± 0.087 Function impaired Yes Yes
[nM/sec] p = 0.0011 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0073
l−/Cl− 0.045 ± 0.005 (3) 0.075 ± 0.015 (3) 0.116 ± 0.020 (3) 0.151 ± 0.011 (3) 0.143 ± 0.010 (3) 0.054 ± 0.007 WT-like
[mM/sec] p = 0.013 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.058
Exon 9 p.F354S
(c.1061T>C)		 HCO3−/Cl− 0.87 ± 0.19 (3) 1.25 ± 0.09 (3) 1.78 ± 0.07 (3) 2.37 ± 0.62 (3) 2.39 ± 0.62 (3) 0.832 ± 0.140 WT-like Yes Yes
[nM/sec] p = 0.0049 p = 0.0002 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.83
l−/Cl− 0.030 ± 0.002 (3) 0.063 ± 0.013 (3) 0.146 ± 0.045 (3) 0.140 ± 0.011 (3) 0.146 ± 0.022 (3) 0.062 ± 0.011 WT-like
[mM/sec] p = 0.42 p = 0.011 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0001 p = 0.30
p.K369E
(c.1105A>G)		 HCO3−/Cl− 0.42 ± 0.01 (3) 0.59 ± 0.10 (4) 0.76 ± 0.05 (4) 0.94 ± 0.11 (4) 1.09 ± 0.13 (3) 0.339 ± 0.029 Function impaired Yes Yes
[nM/sec] p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.032 ± 0.006 (3) 0.056 ± 0.011 (3) 0.070 ± 0.028 (3) 0.104 ± 0.004 (3) 0.104 ± 0.041 (3) 0.038 ± 0.008 Function impaired
[mM/sec] p = 0.29 p = 0.0035 p = 0.0002 p < 0.0001 p < 0.0001 p = 0.0003 p = 0.0013
p.A372V
(c.11150T)		 HCO3−/Cl− 0.072 ± 0.029 (4) 0.064 ± 0.022 (4) 0.081 ± 0.024 (4) 0.076 ± 0.034 (4) 0.069 ± 0.022 (4) 0.001 ± 0.008 Function impaired Yes? No?
[nM/sec] p = 0.063 p = 0.14 p = 0.022 p = 0.040 p = 0.087 p = 0.88 p < 0.0001
l−/Cl− 0.046 ± 0.014 (3) 0.030 ± 0.007 (3) 0.022 ± 0.004 (3) 0.022 ± 0.002 (3) 0.022 ± 0.002 (3) slope < 0 Function impaired
[mM/sec] p < 0.0001 p = 0.033 p = 0.68 p = 0.77 p = 0.78 ns* p < 0.0001
Exon 10 p.N392Y
(c.1174A>T)		 HCO3−/Cl− 0.058 ± 0.019 (3) 0.048 ± 0.015 (3) 0.041 ± 0.015 (3) 0.069 ± 0.024 (3) 0.057 ± 0.007 (3) 0.004 ± 0.006 Function impaired No No
[nM/sec] p = 0.17 p = 0.44 p = 0.78 p = 0.040 p = 0.18 p = 0.56 p < 0.0001
l−/Cl− 0.039 ± 0.014 (3) 0.028 ± 0.006 (3) 0.022 ± 0.006 (3) 0.020 ± 0.007 (3) 0.015 ± 0.005 (3) slope < 0 Function impaired
[mM/sec] p = 0.0006 p = 0.11 p = 0.67 p = 0.86 p = 0.27 ns* p < 0.0001
p.S399P
(c.1195T>C)		 HCO3−/Cl− 0.70 ± 0.12 (3) 1.22 ± 0.21 (3) 1.67 ± 0.36 (3) 1.83 ± 0.40 (3) 2.10 ± 0.12 (3) 0.679 ± 0.096 WT-like Yes Yes
[nM/sec] p = 0.0013 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.16
l−/Cl− 0.050 ± 0.007 (3) 0.096 ± 0.010 (3) 0.132 ± 0.010 (3) 0.146 ± 0.018 (3) 0.150 ± 0.031 (3) 0.050 ± 0.008 Function impaired
[mM/sec] p = 0.0026 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.027
p.S408F
(c.1223C>T)		 HCO3−/Cl− 0.044 ± 0.011 (3) 0.039 ± 0.040 (3) 0.056 ± 0.051 (3) 0.038 ± 0.027 (3) 0.064 ± 0.014 (3) 0.008 ± 0.011 Function impaired Yes Yes
[nM/sec] p = 0.76 p = 0.95 p = 0.41 p = 0.97 p = 0.24 p = 0.47 p < 0.0001
l−/Cl− 0.013 ± 0.001 (3) 0.021 ± 0.002 (3) 0.019 ± 0.002 (3) 0.022 ± 0.002 (3) 0.023 ± 0.003 (3) 0.004 ± 0.001 Function impaired
[mM/sec] < control p = 0.84 p = 0.71 p = 0.65 p = 0.32 p = 0.0011 p < 0.0001
p.R409H
(c.1226G>A)		 HCO3−/Cl− 0.018 ± 0.030 (3) 0.051 ± 0.033 (3) 0.081 ± 0.079 (3) 0.091 ± 0.079 (3) 0.058 ± 0.078 (3) 0.024 ± 0.022 Function impaired Yes Yes
[nM/sec] p = 0.64 p = 0.74 p = 0.30 p = 0.20 p = 0.62 p = 0.29 p < 0.0001
l−/Cl− 0.019 ± 0.006 (3) 0.019 ± 0.008 (3) 0.020 ± 0.003 (3) 0.021 ± 0.010 (3) 0.021 ± 0.006 (3) 0.001 ± 0.002 Function impaired
[mM/sec] p = 0.74 p = 0.65 p = 0.84 p = 0.92 p = 0.84 p = 0.56 p < 0.0001
p.T410K
(c.1229C>A)		 HCO3−/Cl− 0.031 ± 0.030 (3) 0.017 ± 0.022 (3) 0.029 ± 0.010 (3) 0.060 ± 0.021 (3) 0.051 ± 0.029 (3) 0.016 ± 0.009 Function impaired No No
[nM/sec] p = 0.75 p = 0.26 p = 0.65 p = 0.21 p = 0.44 p = 0.078 p < 0.0001
l−/Cl− 0.014 ± 0.010 (3) 0.019 ± 0.007 (3) 0.013 ± 0.000 (3) 0.013 ± 0.004 (3) 0.012 ± 0.001 (3) slope < 0 Function impaired
[mM/sec] p = 0.080 p = 0.72 p = 0.062 p = 0.068 < control p = 0.34 p < 0.0001
p.T410M
(c.1229C>T)		 HCO3−/Cl− 0.062 ± 0.029 (3) 0.088 ± 0.062 (3) 0.095 ± 0.044 (3) 0078 ± 0.049 (3) 0.097 ± 0.035 (3) 0.012 ± 0.015 Function impaired No No
[nM/sec] p = 0.42 p = 0.10 p = 0.073 p = 0.19 p = 0.065 p = 0.44 p < 0.0001
l−/Cl− 0.025 ± 0.006 (3) 0.021 ± 0.004 (3) 0.017 ± 0.004 (3) 0019 ± 0.007 (3) 0.018 ± 0.007 (3) slope < 0 Function impaired
[mM/sec] p = 0.19 p = 0.90 p = 0.37 p = 0.72 p = 0.59 p = 0.14 p < 0.0001
p.T416P
(c.1246A>C)		 HCO3−/Cl− 0.060 ± 0.024 (3) 0.083 ± 0.017 (3) 0.101 ± 0.020 (3) 0.089 ± 0.010 (3) 0.105 ± 0.008 (3) 0.019 ± 0.006 Function impaired No Yes
[nM/sec] p = 0.13 p = 0.0056 p = 0.0005 p = 0.0025 p = 0.0003 p = 0.0098 p < 0.0001
l−/Cl− 0.015 ± 0.001 (3) 0.015 ± 0.002 (3) 0.019 ± 0.002 (3) 0.019 ± 0.001 (3) 0.019 ± 0.005 (3) 0.002 ± 0.001 Function impaired
[mM/sec] p = 0.057 p = 0.090 p = 0.67 p = 0.63 p = 0.60 p = 0.029 p < 0.0001
p.Q421L
(c.1262A>T)		 HCO3−/Cl− 0.28 ± 0.04 (3) 0.44 ± 0.12 (3) 0.54 ± 0.13 (3) 0.57 ± 0.16 (3) 0.52 ± 0.18 (3) 0.121 ± 0.050 Function impaired Yes? Yes
[nM/sec] p = 0.012 p = 0.0003 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.030 p < 0.0001
l−/Cl− 0.031 ± 0.007 (3) 0.040 ± 0.006 (3) 0.045 ± 0.016 (3) 0.050 ± 0.019 (3) 0.058 ± 0.017 (3) 0.013 ± 0.005 Function impaired
[mM/sec] p = 0.16 p = 0.012 p = 0.002 p = 0.0004 p < 0.0001 p = 0.013 p < 0.0001
Exon 11 p.I426N
(c.1277T>A)		 HCO3−/Cl− 0.60 ± 0.21 (3) 0.97 ± 0.24 (3) 1.46 ± 0.16 (3) 1.65 ± 0.21 (3) 1.64 ± 0.29 (3) 0.549 ± 0.090 Function impaired Yes? Yes
[nM/sec] p = 0.0011 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.016
l−/Cl− 0.036 ± 0.005 (3) 0.062 ± 0.012 (3) 0.089 ± 0.002 (3) 0.104 ± 0.013 (3) 0.111 ± 0.003 (3) 0.038 ± 0.004 Function impaired
[mM/sec] p = 0.0032 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0007
p.L445W
(c.1334T>G)		 HCO3−/Cl− 0.077 ± 0.035 (3) 0.102 ± 0.065 (3) 0.127 ± 0.060 (3) 0.070 ± 0.038 (3) 0.079 ± 0.047 (3) slope < 0 Function impaired No No
[nM/sec] p = 0.24 p = 0.065 p = 0.016 p = 0.34 p = 0.22 p = 0.75 p < 0.0001
l−/Cl− 0.018 ± 0.005 (3) 0.012 ± 0.002 (3) 0.011 ± 0.002 (3) 0.016 ± 0.003 (3) 0.013 ± 0.001 (3) slope < 0 Function impaired
[mM/sec] p = 0.43 < control < control p = 0.14 < control p = 0.38 p < 0.0001
Exon 12 p.N457K
(c.1371C>A)		 HCO3−/Cl− 0.29 ± 0.07 (3) 0.52 ± 0.16 (3) 0.74 ± 0.03 (3) 0.88 ± 0.13 (3) 0.89 ± 0.11 (3) 0.313 ± 0.043 Function impaired Yes Yes
[nM/sec] p = 0.0023 p < 0. 001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.035 ± 0.008 (3) 0.051 ± 0.003 (3) 0.073 ± 0.014 (3) 0.079 ± 0.002 (3) 0.074 ± 0.013 (3) 0.021 ± 0.004 Function impaired
[mM/sec] p = 0.0099 p < 0.0001 p < 0.0001 p < 0.001 p < 0.0001 p = 0.0002 p < 0.0001
p.R470H
(c.1409G>A)		 HCO3−/Cl− 0.65 ± 0.18 (5) 1.01 ± 0.27 (5) 1.70 ± 0.60 (5) 2.16 ± 0.78 (5) 2.64 ± 0.81 (5) 1.030 ± 0.156 WT-1ike Yes Yes
[nM/sec] p = 0.086 p = 0.0089 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.19
l−/Cl− 0.065 ± 0.027 (3) 0.098 ± 0.016 (3) 0.135 ± 0.014 (3) 0.197 ± 0.010 (3) 0.224 ± 0.071 (3) 0.083 ± 0.012 WT-1ike
[mM/sec] p = 0.013 p = 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.45
Exon 13 p.V483E
(c.1448T>A)		 HCO3−/Cl− 0.32 ± 0.13 (3) 0.95 ± 0.19 (3) 1.40 ± 0.25 (3) 1.42 ± 0.22 (3) 1.62 ± 0.15 (3) 0.609 ± 0.092 WT-1ike Yes? Yes
[nM/sec] p = 0.033 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0004 p = 0.052
l−/Cl− 0.049 ± 0.023 (3) 0.089 ± 0.025 (3) 0.131 ± 0.050 (3) 0.148 ± 0.014 (3) 0.148 ± 0.021 (3) 0.051 ± 0.011 Function impaired
[mM/sec] p = 0.052 p = 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0004 p = 0.046
p.G497S
(c.1489G>A)		 HCO3−/Cl− 0.11 ± 0.04 (3) 0.14 ± 0.02 (3) 0.22 ± 0.05 (3) 0.26 ± 0.07 (3) 0.27 ± 0.13 (3) 0.084 ± 0.024 Function impaired Yes? Yes
[nM/sec] p = 0.13 p = 0.037 p = 0.0017 p = 0.0003 p = 0.0002 p = 0.0042 p < 0.0001
l−/Cl− 0.019 ± 0.004 (4) 0.030 ± 0006 (4) 0.037 ± 0.009 (4) 0.048 ± 0.007 (4) 0.045 ± 0.005 (4) 0.014 ± 0.002 Function impaired
[mM/sec] p = 0.65 p = 0.011 p = 0.9001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
C-terminal domain (CTD) Exon 14 p.T527P
(c.1579A<C)		 HCO3−/Cl− 0.17 ± 003 (3) 0.44 ± 0.09 (3) 0.66 ± 0.19 (3) 0.78 ± 0.14 (3) 0.91 ± 0.24 (3) 0.362 ± 0.054 Function impaired Yes Yes
[nM/sec] p = 0.19 p = 0.0010 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0001
l−/Cl− 0.023 ± 0.007 (4) 0.056 ± 0.014 (4) 0.088 ± 0.014 (4) 0.095 ± 0.027 (4) 0.100 ± 0.023 (4) 0.039 ± 0.006 Function impaired
[mM/sec] p = 0.76 p = 0.0004 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0003
p.l529S
(c.1586T>G)		 HCO3−/Cl− 0.18 ± 0.04 (5) 0.28 ± 0.10 (5) 0.36 ± 0.10 (5) 0.40 ± 0.09 (5) 0.46 ± 0.12 (5) 0.139 ± 0.025 Function impaired Yes Yes
[nM/sec] p = 0.016 p = 0.0002 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.028 ± 0.007 (3) 0.042 ± 0.012 (3) 0.060 ± 0.004 (3) 0.065 ± 0.017 (3) 0.064 ± 0.003 (3) 0.019 ± 0.004 Function impaired
[mM/sec] p = 0.18 p = 0.0006 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0003 p < 0.0001
Exon 15 p.Y556C
(c.1667A>G)		 HCO3−/Cl− 0.053 ± 0.041 (5) 0.082 ± 0.017 (5) 0.10 ± 0.03 (5) 0.13 ± 0.05 (5) 0.17 ± 0.05 (5) 0.056 ± 0.011 Function impaired Yes? Yes
[nM/sec] p = 0.53 p = 0.081 p = 0.016 p = 0.0006 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.011 ± 0.004 (3) 0.017 ± 0.002 (3) 0.020 ± 0.006 (3) 0.022 ± 0.003 (3) 0.025 ± 0.007 (3) 0.006 ± 0.002 Function impaired
[mM/sec] < control p = 0.33 p = 0.86 p = 0.76 p = 0.22 p = 0.0017 p 0.0001
p.C565Y
(c.1694G>A)		 HCO3−/Cl− 0.73 ± 0.07 (3) 1.06 ± 0.16 (3) 1.55 ± 0.05 (3) 1.86 ± 0.30 (3) 2.07 ± 0.37 (3) 0.696 ± 0.077 WT-11ke Yes Yes
[nM/sec] p = 0.0091 p = 0.0059 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.19
l−/Cl− 0.043 ± 0.019 (3) 0.044 ± 0.012 (3) 0.064 ± 0.014 (3) 0.108 ± 0.017 (3) 0.131 ± 0.017 (3) 0.048 ± 0.006 Function impaired
[mM/sec] p = 0.0002 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0142
Exon 17 p.S657N
(c.1970G>A)		 HCO3−/Cl− 0.38 ± 007 (3) 0.67 ± 0.14 (3) 0.83 ± 0.12 (3) 0.91 ± 0.11 (3) 0.97 ± 0.18 (3) 0.284 ± 0.049 Function impaired Yes Yes
[nM/sec] p = 0.0007 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.020 ± 0.003 (3) 0.042 ± 0.017 (3) 0.060 ± 0.012 (3) 0.086 ± 0.016 (3) 0.095 ± 0.012 (3) 0.039 ± 0.004 Function impaired
[mM/sec] p = 0.97 p = 0.0034 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0009
p.V659L
(c.1975G>C)		 HCO3−/Cl− 0.59 ± 0.12 (5) 0.82 ± 0.18 (5) 0.90 ± 0.09 (5) 1.17 ± 0.38 (5) 1.23 ± 0.33 (5) 0.326 ± 0.067 Function impaired Yes Yes
[nM/sec] p = 0.0008 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
l−/Cl− 0.048 ± 0.003 (3) 0.086 ± 0.005 (3) 0.081 ± 0.022 (3) 0.111 ± 0.018 (3) 0.096 ± 0.011 (3) 0.024 ± 0.007 Function impaired
[mM/sec] p = 0.0008 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0031 p < 0.0001
p.S666F
(c.1997C>T)		 HCO3−/Cl− 0.19 ± 0.05 (3) 0.32 ± 0.07 (3) 0.43 ± 0.15 (3) 0.53 ± 0.19 (3) 0.47 ± 0.12 (3) 0.153 ± 0.045 Function impaired No? Yes
[nM/sec] p = 0.069 p = 0.0032 p = 0.0002 p < 0.0001 p < 0.0001 p = 0.0050 p < 0.0001
l−/Cl− 0.030 ± 0.002 (3) 0.039 ± 0.007 (3) 0.053 ± 0.009 (3) 0.065 ± 0.022 (3) 0.073 ± 0.008 (3) 0.022 ± 0.004 Function impaired
[mM/sec] p = 0.12 p = 0.0052 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
p.D669E
(c.2007C>A)		 HCO3−/Cl− 0.054 ± 0.020 (5) 0.073 ± 0.043 (5) 0.073 ± 0.033 (5) 0.070 ± 0.030 (5) 0.057 ± 0.046 (5) 0.000 ± 0.010 Function impaired No? Yes
[nM/sec] p = 0.46 p = 0.11 p = 0.11 p = 0.15 p = 0.37 p = 0.96 p < 0.0001
l−/Cl− 0.014 ± 0.006 (3) 0.013 ± 0.006 (3) 0.014 ± 0.007 (3) 0.016 ± 0.004 (3) 0.016 ± 0.004 (3) 0.001 ± 0.002 Function impaired
[mM/sec] p = 0.083 p = 0.063 p = 0.097 p = 0.21 p = 0.23 p = 0.48 p < 0.0001
Exon 18 p.F683S
(c.2048T>C)		 HCO3−/Cl− 0.012 ± 0.021 (3) 0.051 ± 0.002 (3) 0.022 ± 0.023 (3) 0.052 ± 0.013 (3) 0.071 ± 0.095 (3) 0.024 ± 0.015 Function impaired No Yes
[nM/sec] p = 0.41 p = 0.64 p = 0.61 p = 0.63 p = 0.27 p = 0.15 p < 0.0001
l−/Cl− 0.013 ± 0.010 (3) 0.010 ± 0.005 (3) 0.008 ± 0.001 (3) 0.008 ± 0.002 (3) 0.012 ± 0.005 (3) slope < 0 Function impaired
[mM/sec] < control < control < control < control < control p = 0.85 p < 0.0001
p.F692L
(c.2074T>C)		 HCO3−/Cl− 0.42 ± 0.18 (5) 0.68 ± 0.23 (5) 0.78 ± 0.26 (5) 1.02 ± 0.47 (5) 1.03 ± 0.26 (5) 0.310 ± 0.080 Function impaired No No
[nM/sec] p = 0.034 p = 0.0010 p = 0.0002 p < 0.0001 p < 0.0001 p = 0.0008 p < 0.0001
l−/Cl− 0052 ± 0011 (3) 0.083 ± 0.015 (3) 0.112 ± 0.020 (3) 0.117 ± 0.038 (3) 0.110 ± 0.026 (3) 0.030 ± 0.009 Function impaired
[mM/sec] p = 0.0108 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 p = 0.0059 p = 0.0001
Exon 19 p.L703P
(c.2108T>C)		 HCO3−/Cl− 0.036 ± 0.029 (5) 0.044 ± 0.027 (5) 0.041 ± 0032 (5) 0.056 ± 0.024 (5) 0038 ± 0027 (5) 0.003 ± 0.008 Function impaired No Yes
[nM/sec] p = 0.93 p = 0.68 p = 0.81 p = 0.28 p = 0.97 p = 0.69 p < 0.0001
l−/Cl− 0.022 ± 0.018 (4) 0.024 ± 0.014 (4) 0.032 ± 0.034 (4) 0.020 ± 0.014 (4) 0.023 ± 0.017 (4) slope < 0 Function impaired
[mM/sec] p = 0.87 p = 0.74 p = 0.23 p = 0.99 p = 0.83 p = 0.94 p < 0.0001
p.T721M
(c.2162C>T)		 HCO3−/Cl− 0.10 ± 0.05 (4) 0.14 ± 0.04 (4) 0.12 ± 0.06 (4) 0.13 ± 0.05 (4) 0.12 ± 0.05 (4) 0.005 ± 0.015 Function impaired No Yes
[nM/sec] p = 0.045 p = 0:0043 p = 0.016 p = 0.0090 p = 0.0139 p = 0.75 p < 0.0001
l−/Cl− 0.017 ± 0.005 (3) 0.022 ± 0.004 (3) 0.020 ± 0.004 (3) 0.019 ± 0.002 (3) 0.025 ± 0.004 (3) 0.003 ± 0.001 Function impaired
[mM/sec] p = 0.34 p = 0.64 p = 0.87 p = 0.74 p = 0.16 p = 0.11 p < 0.0001
p.H723R
(c.2168A>G)		 HCO3−/Cl− 0.29 ± 0.11 (4) 0.35 ± 0.11 (4) 0.43 ± 0.18 (4) 0.45 ± 0.21 (4) 0.53 ± 0.25 (4) 0.115 ± 0.053 Function impaired No Yes
[nM/sec] p = 0.032 p = 0.0095 p = 0.0019 p = 0.0013 p = 0.0002 p = 0.042 p < 0.0001
l−/Cl− 0.038 ± 0.013 (3) 0.017 ± 0.005 (3) 0.020 ± 0.012 (3) 0.025 ± 0.005 (3) 0.029 ± 0.008 (3) slope < 0 Function impaired
[mM/sec] p = 0.019 p = 050 p = 0.06 p = 0.35 p = 0.085 p = 0.67 p < 0.0001