. Author manuscript; available in PMC: 2011 Jun 1.

Published in final edited form as: Expert Rev Cardiovasc Ther. 2010 Aug;8(8):1161–1173. doi: 10.1586/erc.10.89

Table 1.

Mutations associated with trafficking defects in cardiac arrhythmia.

Gene	Disease	Mutations	Proposed mechanism	Ref.
KCNQ1	LQT1	Y148X	Channel truncation	[55]
		A178fs/105	^†	[56]
		L191P	Exposure of a hydrophobic residue	[102]
		H258R	^†	[59]
		E261D	^†	[57]
		E261K	^†	[57]
		L273F	^†	[57]
		F275S	^†	[103]
		ΔS276	^†	[55]
		Q357R	^†	[104]
		R518X	^†	[57]
		M520R	Impaired calmodulin interaction	[105]
		Q530X	^†	[57]
		T587M	Blocks interaction with hERG	[61]
		G589D	Disruption of a trafficking motif	[106]
		R591H	Disruption of a trafficking motif	[106]
		R594Q	Disruption of a trafficking motif	[106]
		ΔV595	Impaired subunit assembly	[58]
		R863X	Channel truncation	[107]
		P631fs/19	Generation of an RXR retention motif	[58]
		1008delC	^†	[57]
KCNH2	LQT2	I31S	^†	[33]
		T65P	PAS domain disruption	[108]
		del234–241	^†	[109]
		A422T	^†	[33]
		A429P	^†	[109]
		D456Y	^†	[33]
		F463L	^†	[77]
		N470D	^†	[33]
		T474I	^†	[33]
		Y493F	^†	[109]
		R534C	^†	[33]
		A561T	^†	[33]
		A561V	^†	[33]
		H562P	^†	[33]
		I571L	^†	[33]
		G572S	^†	[33]
KCNH2	LQT2	I593R	Activates the UPR pathway	[37]
		P596R	^†	[33]
		G601S	Altered chaperone interactions that promote degradation	[31]
		G604S	^†	[110]
		Y611H	^†	[33]
		V612L	^†	[33]
		A614V	^†	[33]
		T623I	^†	[33]
		N629D	^†	[33]
		N629S	^†	[33]
		V630A	^†	[33]
		V630L	^†	[33]
		F640V	^†	[33]
		R725W	Strengthened interaction with ER-associated chaperones	[40]
		Q725X	Channel truncation with impaired subunit assembly	[111]
		R744fs	^†	[112]
		2398+1G>C	18 amino acid insertion that disrupts CNBD	[113]
		F805C	^†	[33]
		S818L	^†	[33]
		V822M	^†	[33]
		R823W	^†	[33]
		p.Pro872fs	Channel truncation that retains WT channel intracellularly	[114]
		A915fs+47X	^†	[115]
		R1014X	Channel truncation	[45]
		1122fs/147	^†	[116]
SCN5A	Brugada	R282H	^†	[117]
		T353I	^†	[118]
		E1053K	Impaired interaction with ankyrin-G	[119]
		R1232W/ T1620M	^†	[120] [121]
		G1406R	^†	[122]
		R1432G	^†	[123]
		G1734R	^†	[124]
		M1766L	^†	[125]
	CCD	5280delG	Misfolding	[126]
SCN5A	CCD	P1008S	^†	[127]
SCN3B	IVF	V54G	Intracellular retention of Nav1.5	[128]
GPD1- L	Brugada	A280V	Intracellular retention of Nav1.5	[129]
ANKB	LQT4	E1425G	Loss of ion channel coordination	[68]
KCNE1	LQT5	L51H	Misfolding and retention by quality control mechanisms	[130]
		T58P/L59P	Disrupted KCNQ1 interaction	[131]
		R98W	Disrupted KCNQ1 interaction	[131]
KCNJ2	Andersen syndrome	Δ95–98	^†	[62]
		C101R	^†	[132]
		V302M	Loss of PIP₂ binding	[63]
		Δ314–315	^†	[62]
CACNA1C	LQT8	A39V	^†	[66]
Cav-3	LQTS	T78K	^†	[67]
HCN4	SND	G480R	^†	[133]
		D533N	^†	[134]
CACNB2b	CCD	D601E	^†	[127]

^†

Mechanism is unknown.

CCD: Cardiac conduction disorder; CNBD: Cyclic nucleotide binding domain; ER: Endoplasmic reticulum; IVF: Idiopathic ventricular fibrillation; LQT1: Long QT syndrome type 1; LQT2: Long QT syndrome type 2; LQTS: Long QT syndrome; PAS: Per–Arnt–Sim; PIP₂: Phosphatidylinositol-4,5-bisphosphate; SND: Sinus node dysfunction; UPR: Unfolded protein response; WT: Wild-type.