E. Ficker et al., Retention in the endoplasmic reticulum as a mechanism of dominant-negativecurrent suppression in human long QT syndrome, J MOL CEL C, 32(12), 2000, pp. 2327-2337
Mutations in the cardiac potassium channel HERG (KCNH2) cause chromosome 7-
linked long QT syndrome (LQT2) characterized by a prolonged QT interval, re
current syncope and sudden cardiac death. Most mutations in HERG exhibit "l
oss of function" phenotypes with defective channels either inserted into th
e plasma membrane or retained in the endoplasmic reticulum. "Loss of functi
on" mutations reduce I-Kr, the cardiac delayed rectifier current encoded by
HERG, due to haploinsufficiency or suppression of wild-type function by a
dominant-negative mechanism. One explanation for dominant-negative current
suppression is that mutant subunits render tetrameric channel complexes non
-conducting on co-assembly. In the present paper we describe an alternative
mechanism for this phenomenon. We show (1) that the dominant-negative HERG
mutation A561V is retained in the endoplasmic reticulum and (2) that wild-
type channels are tagged for retention in the ER by co-assembly with traffi
cking deficient A561V subunits. Thus, in HERG A561V dominant-negative suppr
ession of wild-type function is the result of an acquired trafficking defec
t. (C) 2000 Academic Press.