Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen

Abstract

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

“…Tyson et al note that frameshift/truncating mutations affecting the C-terminal domain of KCNQ1 represent a large number of JLNS mutations, in contrast to the more prevalent missense mutations of RWS, spread throughout a variety of domains. 28 Double mutants (homozygotes) of LQT2 and 3, yielding ion channel knock-outs, exhibit a more severe phenotype than their single gene counterparts, and can result in intrauterine and neonatal complications.…”

Counting membrane-embedded KCNE β-subunits in functioning K + channel complexes

“…To regulate cellular potassium flow in both excitable and nonexcitable tissues, Q1 channels coassemble with regulatory KCNE peptides, forming membraneembedded K ϩ channel complexes with various voltage-sensing and gating properties (1). The importance of forming a properly assembled Q1-KCNE complex is underscored by the mutations that give rise to long QT syndrome and congenital hearing loss (2,3). Although the fourfold arrangement of the Q1 ␣-subunits along the ion conduction pathway is established and unquestioned, the number of KCNE ␤-subunits in the K ϩ channel complex has been a long-standing and heated debate (4-7).…”

KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression

“…The biological importance of the proper Q1-E1 complex formation is further underscored by the inherited mutations in either Q1 or E1 that disrupt the assembly and/or trafficking of the complex and give rise to cardiac arrhythmias, most notably long QT syndrome (11). An autosomal recessive form of long QT syndrome also causes neural deafness (12).…”