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Background: The majority of patients with inherited haemochromatosis carry two mutant alleles of the recently discovered HFE gene. Individuals heterozygous for the HFE mutation could be predisposed to end-stage liver disease due to other causes. Methods: The frequencies of the HFE gene mutations C282Y and H63D were determined in DNA samples obtained from 189 liver transplant patients and 225 healthy Finnish blood donors. Results: 5% of the 189 liver transplant recipients were heterozygotes and 0.5% homozygotes for the C282Y mutation, while 16% were heterozygotes and 0.5% homozygotes for the H63D mutation. These figures were not increased in comparison to controls, of whom 11% were C282Y heterozygotes, 16% H63D heterozygotes and 0.9% H63D homozygotes. Among recipients with acute non-A-E hepatitis (n = 31), the frequency of the H63D allele was higher than in controls (21% versus 9.1%, P < 0.01). Perls' stain for iron in explanted liver specimens was positive in 28% of recipients with alcoholic cirrhosis, 26% of patients with acute non-A-E hepatitis and 14% in the rest of the recipients. The HFE genotypes did not correlate with the iron status. Conclusion: Individuals heterozygous for either the C282Y or H63D mutation of the HFE gene are not at increased risk of developing chronic endstage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminant non-A-E hepatitis. [ABSTRACT FROM AUTHOR]

Background: The most prevalent LQT1 form of inherited long QT syndrome is caused by mutations of the KCNQ1 gene resulting repolarizing I(Ks) potassium current to decrease and the QT interval to prolong. As abrupt sympathetic activation triggers ventricular arrhythmias that may cause syncopal attacks and sudden death in LQT1 patients, we investigated whether two known beta1-adrenergic receptor polymorphisms were associated with the duration of QT interval or history of symptoms in LQT1., Methods: We determined beta1-adrenergic receptor polymorphisms (Ser49Gly and Arg389Gly) in 168 LQT1 patients. We also reviewed each patient's clinical records on the history of long QT syndrome-related symptoms and measured QT intervals from baseline ECG in each subject and from an exercise test ECG in 55 LQT1 patients., Results: Patients with the homozygous Arg389Arg genotype tended to have shorter and those with the Ser49Ser genotype longer QT intervals than patients with other genotypes, but neither polymorphism studied alone affected the risk of symptoms. In contrast, adjusted odds ratio for the history of symptoms was 4.9 (95% CI 1.18 to 20.3) in patients homozygous for both Ser49 and Arg389. These double homozygous patients showed similar QT intervals as the rest of the LQT1 cohort., Conclusions: In this relatively small study, double homozygosity for Arg389 and Ser49 of the human beta1-adrenergic receptor associated with the risk of symptoms in LQT1. The association between these beta1-adrenergic receptor polymorphisms and the symptom history in LQT1 is not mediated via QT interval duration.

Background: Mutations in five cardiac voltage-gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long-QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LOTS-causing mutations in 92 Finnish families., Aim: In order to complete the characterization of Finnish spectrum of LOTS genes, we conducted a systematic search for mutations in the five LOTS genes among 188 additional unrelated probands., Methods: The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing., Results: Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LOTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7-2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases., Conclusions: The extent of genetic homogeneity underlying LOTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LOTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease.

Objectives: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS., Background: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family., Methods: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique., Results: We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively., Conclusions: A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Background: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2])., Methods and Results: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders., Conclusions: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.