A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.

TY - JOUR

T1 - A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.

AU - Schmitt, N

AU - Schwarz, M

AU - Peretz, A

AU - Abitbol, I

AU - Attali, B

AU - Pongs, O

N1 - Keywords: Amino Acid Sequence; Animals; CHO Cells; Cloning, Molecular; Cricetinae; Electrophysiology; Genes, Recessive; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome; Microinjections; Molecular Sequence Data; Mutation; Oocytes; Potassium Channels; Potassium Channels, Voltage-Gated; RNA, Complementary; Sequence Alignment; Transfection; Xenopus

PY - 2000

Y1 - 2000

N2 - The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K(+) channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly. The results provide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel. Udgivelsesdato: 2000-Feb-1

AB - The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K(+) channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly. The results provide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel. Udgivelsesdato: 2000-Feb-1

U2 - 10.1093/emboj/19.3.332

DO - 10.1093/emboj/19.3.332

M3 - Journal article

C2 - 10654932

SN - 0261-4189

VL - 19

SP - 332

EP - 340

JO - E M B O Journal

JF - E M B O Journal

IS - 3

ER -