Novel mutations of KCNQ1 in Long QT syndrome

Abstract

Background: Autosomal recessive Long QT syndrome is characterized by prolonged QTc along with congenital bilateral deafness depends on mutations in K(+) channel genes. A family of a Long QT syndrome proband from India has been identified with novel indel variations.

Methods: The molecular study of the proband revealed 4 novel indel variations in KCNQ1. In-silico analysis revealed the intronic variations has led to a change in the secondary structure of mRNA and splice site variations. The exonic variations leads to frameshift mutations. DNA analysis of the available family members revealed a carrier status.

Results and conclusion: It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2-S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.

Keywords: 3D KCNQ1 structure; Family study; JLN syndrome; Long QT syndrome; Novel mutations.

Fig. 1

Pedigree of proband.

Fig. 2

Electrocardiogram of LQTS proband showing a prolonged QT_C of 520 msec.

Fig. 3

A: SSCP pattern of Exon-3 of KCNQ1 Lane 1–8 in order (from left): Control, proband, father, mother, sibling, maternal grandmother, maternal grandfather, paternal grandmother. B: SSCP pattern of Exon-4 of KCNQ1 Lane 1–8 in order (from left): Control, maternal grandmother, maternal grandfather, paternal grandmother, proband, father, mother and sibling.

Fig. 4

(A–G): Electropherogram of control (A) and mutant (B) revealed the deletion of ‘G’ at −20 and insertion of ‘CAAGG’ between −19 and −18 upstream of Exon 3 i.e. in Intron 3. electropherogram of control (C) and mutant (D) revealing an insertion of ‘ATC’ in Exon 3. electropherogram of control (E) and mutant (F) showing the deletion of ‘G’ in Exon 4, the chromatogram of maternal heterozygous sample (G), paternal heterozygous sample (H), sibling heterozygous sample (I).

Fig. 5

The change in binding sites of various proteins. As seen clearly there is change in binding sites of various proteins (A-wild type and B-mutant) that play a role in regulation (refer Table 2).

Fig. 6

A: Wild type protein secondary structure encoded by 3rd exon. B: Mutant protein secondary structure encoded by 3rd exon. C: Wild type protein secondary structure encoded by 4th exon. D: Mutant protein secondary structure encoded by 4th exon.

Fig. 7

A: 3D structure of mutant protein. B: 3D structure of wild type protein.

Fig. 8

A: Transmembrane structure of wild-type protein. B: transmembrane structure of mutant (Exon 3 + Exon 4 variations) protein.