Three novel mutations in exon 21 encoding beta-cardiac myosin heavy chain.

Familial hypertrophic cardiomyopathy has a complex multigenic background. Previous work allowed to determine one of the gene loci responsible for this disease on chromosome 14 band q11-q12, and linked it to the alpha and beta-cardiac myosin heavy chains. In this study we demonstrate changes in exon 21, coding for beta-myosin heavy chain. We described 4 patients from different families with an unequivocal diagnosis of hypertrophic cardiomyopathy based on the clinical picture. Direct sequencing of exon 21 revealed the presence of 5 novel mutations. Two of the mutations in codons 771 and 781 revealed in our study did not result in any changes in amino acid sequence. The next three were as follows: in codon 782 (AGC > GAC) transition responsible for Ser-->Asp substitution; in codon 779 (GAG > TAG) mutation that results in replacement of Glu-->Stop; in codon 774 (GAG > GTG) which is expressed as substitution of Glu-->Val. These mutations are located close to mutations identified and described in the literature, so they are likely to cause similar symptoms.

KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome.

KCNQ1 (formerly called KVLQT1) is a Shaker-like voltage-gated potassium channel gene responsible for the LQT1 sub-type of LQTS. In general, heterozygous mutations in KCNQ1 cause Romano-Ward syndrome (LQT1 only), while homozygous mutations cause JLNS (LQT1 and deafness). To date, more than 100 families with mutations in this gene have been reported, most with their own novel 'private' mutations. The majority of these mutations are missense. However, other types of mutations, such as deletions, frame-shifts and splice-donor errors have also been reported. There is one frequently reported mutated region (the 'hot-spot'). KCNQ1 is now believed to be the most commonly mutated gene in LQTS. The combination of normal and mutant KCNQ1 alpha-subunits has been found to form abnormal IKS channels, hence mutations associated with the KCNQ1 gene are also believed to act mainly through a dominant-negative mechanism (the mutant form interferes with the function of the normal wild-type form through a 'poison pill' type mechanism) or loss of function mechanism. Even in the case of carriers of the same mutation, it is currently unknown why there are significant clinical phenotype variations in LQT1 patients. This question could be answered by increasing the number of patient genotypes studied. LQT1 patients experience a majority of their cardiac events (62%) during exercise, and only 3% occur during rest or sleep. Of the patients who experienced cardiac events while swimming, 99% were LQT1. Auditory stimuli are rare and occur in only 2% of patients. However, both lethal and non-lethal events follow the same pattern.

The KVLQT1 gene is not a common target for mutations in patients with various heart pathologies.

The long QT syndrome (LQTS) is a disorder of ventricular repolarization that exposes affected individuals to cardiac arrhythmias and sudden death. The first gene for LQTS has been mapped to chromosome 11 p.15.5 by genome-wide linkage analysis. This gene, originally named KVLQT1 (and later KCNQ1), is a novel potassium channel gene. Mutations in the human KVLQT1 gene, encoding the alpha-subunit of the KVLQT1 channel, cause the long QT syndrome. In this work, we analysed the sequence of six KVLQT1 exons in patients with various heart pathologies. We describe 6 different mSSCP patterns with no disease-related SSCP conformers in any sample. Direct sequencing of exons 2 to 7 confirmed the absence of mutations. This suggests that the analysed region of the KVLQT1 gene is not commonly involved in pathogenesis of the long QT syndrome.