Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Table 2 KCNK9 variants in this study assessed for TASK3 structure- and dynamics-based changes

Protein variant	ΔΔG_fold	ΔFour-body Pot.	ΔSRLF	ΔPC ^a	Transport events ^b	ΔElec surface	Selectivity Filter [K⁺] ^c	Δ[K⁺] ^c	Blinded prediction ^d
R131S	1.36 ± 0.17	− 2.63	1.13	PC2 (2.6σ)	8	+	0.39	–––	Occluded-permissive
R131H	1.05 ± 0.17	− 1.48	1.26	n.s.	4	+	1.42	–	Mixed-permissive
R131P	6.87 ± 0.65	4.34	− 0.71	PC2 (− 1.1σ) PC3 (1.5σ)	10	--	1.08	––	Mono-permissive
M132R	2.74 ± 0.10	14.77	− 1.21	PC3 (− 1.1σ)	14	n.s	2.30	+	Mixed-permissive
F135del	NA	NA	NA	PC3 (− 2.4σ)	9	n.s	1.52	–	Mixed-permissive
M156V	2.54 ± 0.17	− 3.75	1.22	n.s.	6	+	0.62	–––	Permissive
M159I	8.01 ± 0.52	− 22.18	0.86	n.s.	8	+	1.93	n.s	Permissive
F164C	3.48 ± 0.43	− 31.18	− 0.55	PC1 (1.2σ)	8	n.s	2.92	++	Permissive
T199A	0.92 ± 0.14	1.83	0.08	PC2 (− 2.7σ) PC3 (2.3 )	12	+	1.93	n.s	Permissive
Y205C	4.01 ± 0.63	− 5.57	2.94	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
G236R	− 2.59 ± 0.54	− 3.41	− 0.46	PC2 (− 2.8σ) PC3 (1.6σ)	0	++	0.25	–––	Occluded
G236R & A237T	− 2.40 ± 0.54	0.32	NA	PC1 (− 2.0σ) PC3 (− 2.4σ)	10	++	0.81	––	Occluded-attenuated
A237D	5.36 ± 0.17	13.51	− 1.85	PC2 (− 1.3σ)	8	n.s	1.37	–	Permissive
A237T	0.13 ± 0.07	− 0.60	− 0.76	PC2 (− 2.9σ)	4	+	1.80	n.s	Moderately permissive
M249T	6.41 ± 0.83	5.09	0.59	PC2 (− 3.1σ) PC3 (1.2σ)	1	--	2.00	n.s	Permissive

SRLF single residue level frustration, NA not applicable, n.d. not determined
^a PC alterations of at least 1 standard deviation (σ) away from WT are noted; others are labeled as not significant (n.s.); data used ignored the C-terminus (see Methods)
^b Compared to a WT value of 2 transport events
^c Defined based on the K⁺ radial distribution functions (Fig. S4 and S5) at 6.9 Å from residues 94 and 200. Comparisons are to the WT value of 1.8
^d Using only the computational simulation data, we predict if the variants will impair potassium transport or not

ISSN: 1756-994X