Jens Mogensen

Risk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers A European Cohort Study

OBJECTIVESnThe purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers.nnnBACKGROUNDnLMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA.nnnMETHODSnIn this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment.nnnRESULTSnIn a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor.nnnCONCLUSIONSnCarriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.

An improved method for chromosome-specific labeling of α satellite DNA in situ by using denatured double-stranded DNA probes as primers in a primed in situ labeling (PRINS) procedure

An improved primed in situ labeling (PRINS) procedure that provides fast, highly sensitive, and nonradioactive cytogenetic localization of chromosome-specific tandem repeat sequences is presented. The PRINS technique is based on the sequence-specific annealing in situ of unlabeled DNA. This DNA then serves as primer for chain elongation in situ catalyzed by a DNA polymerase. If biotin-labeled nucleotides are used as substrate for the chain elongation, the hybridization site becomes labeled with biotin. The biotin is subsequently made visible through the binding of FITC-labeled avidin. Tandem repeat sequences may be detected in a few hours with synthetic oligonucleotides as primers, but specific labeling of single chromosomes is not easily obtained. This may be achieved, however, if denatured double-stranded DNA fragments from polymerase-chain-reaction products or cloned probes are used as primers. In the latter case, single chromosome pairs are stained with a speed and ease (1 h reaction and no probe labeling) that are superior to traditional in situ hybridization. Subsequent high-quality Q banding of the chromosomes is also possible. The developments described here extends the range of applications of the PRINS technique, so that it now can operate with any type of probe that is available for traditional in situ hybridization.

Fast one-step procedure for the detection of nucleic acids in situ by primer-induced sequence-specific labeling with fluorescein-12-dUTP

We provide fast, simple, one-step procedures for sequence-specific detection of nucleic acids in situ. Tandem repeat sequences in DNA are stained within 30 min, and mRNA is stained within 2 h. The procedures are based on the incorporation of the newly available fluorescein-labeled dUTP into DNA synthesized in situ by primed in situ labeling, with denatured fragments of cloned DNA or oligonucleotides as primers. The extreme speed and simplicity of the reaction make it attractive for automatization in routine laboratory procedures and opens up new diagnostic possibilities.

Role of genotyping in risk factor assessment for sudden death in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a major cause of premature sudden death in the young, a fact made all the more unsettling to affected families and physicians by the frequent absence of symptoms prior to death [(1)][1]. Published annual sudden death rates have varied as a function of the patient

Hypertrophic cardiomyopathy-the clinical challenge of managing a hereditary heart condition.

See doi:10.1016/S1095-668X(00)00522-5for the article to which this editorial refers. nnWithin this issue of the European Heart Journal van Lange and coworkers investigated current genetic knowledge and practice of Dutch cardiologists regarding counselling and DNA-testing of familial hypertrophic cardiomyopathy (HCM). The study revealed that Dutch cardiologists regarded their genetic knowledge as insufficient and demonstrated that a substantial proportion of HCM patients did not receive adequate information about the hereditary nature of their disease. In addition clinical investigations of relatives at risk of having inherited the disease and genetic analysis to identify disease-causing mutations in affected families were seldom initiated. The authors concluded that the current genetic care for HCM patients is poor and that knowledge needs to be enhanced by improved education of medical students and cardiologists and development of specialised clinics.nnHCM is the most common inherited cardiac condition with a prevalence in young adults of at least 1:500. The condition is diagnosed by demonstration of unexplained thickening of the left ventricle. Disease manifestations typically develop during adolescence although clinical presentation may occur at any age.1 The clinical expression is heterogeneous and varies even between related individuals carrying identical mutations.2 The major clinical problems are reduced exercise capacity, risk of arrhythmia, thrombo-embolic events, and sudden death. Patients at high risk of sudden death can be identified by non-invasive evaluation and treatment with …

Refined localization1 of the human α-tropomyosin gene (TPM1) by genetic mapping

The ·-tropomyosin polypeptide (encoded by the gene TPM1) is expressed in skeletal muscle and is the most abundant tropomyosin in the adult heart (Muthuchamy et al., 1993). It stiffens and stabilizes the thin filaments and has a regulatory influence on the Ca++ dependent interaction between actin and myosin. The ·-tropomyosin gene (TPM1) is one among seven different disease causing genes in families suffering from hypertrophic cardiomyopathy (HCM). However, linkage analysis of TPM1 in HCM-families has been hampered by imprecise and inconsistant mapping results. In order to improve linkage analysis of TPM1 in HCM-families, we have localized the gene in a 3.2-cM interval by genetic mapping.

Troponin Mutations in Cardiomyopathies

Cardiomyopathies are a group of cardiac disorders characterized by structural and functional abnormalities of the myocardium of unexplained aetiology. By convention idiopathic cardiomyopathies are divided into 4 different diagnostic entities: Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM) and arrythmogenic right ventricle cardiomyopathy (ARVC) (Figure 18.1).1 Recent investigations have revealed that the conditions in many cases are hereditary.2, 3, 4

Assignment1 of the human skeletal muscle {FC12}a-actin gene (ACTA1) to chromosome 1q42.13→q42.2 by radiation hybrid mapping

Actin is the major component of the thin filaments in muscle sarcomers and is responsible for muscle contraction by interaction with myosin. The skeletal muscle ·-actin polypeptide is encoded by the ACTA1 gene. It is expressed in skeletal muscle and comprises about 60% of heart ventricular actin (Boheler et al., 1991). Mutations in seven different genes encoding sarcomeric polypeptides are known to cause the dominantly inherited disease hypertrophic cardiomyopathy (HCM) (Towbin, 1998). However, a substantial number of HCM-families show no linkage to these genes. ACTA1 is an obvious HCM candidate gene by encoding a heart sarcomer polypeptide. In order to allow linkage analysis of ACTA1 in HCM-families, we have localized the gene relative to flanking polymorphic markers.