Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy.

Introduction: The minimum criterion for the diagnosis of hypertrophic cardiomyopathy (HCM) is thickening of the left ventricular wall, typically in an asymmetrical or focal fashion, and it requires no functional deficit. Using this criterion, we identified a family with four affected individuals and a single unrelated individual essentially with restrictive cardiomyopathy (RCM). Mutations in genes coding for the thin filaments of cardiac muscle have been described in RCM and HCM with 'restrictive features'.

Ascribing novel functions to the sarcomeric protein, myosin binding protein H (MyBPH) in cardiac sarcomere contraction.

Myosin binding protein H (MyBPH) is a protein of unknown function, which shares sequence and structural similarities with myosin binding protein C (cMyBPC), a protein frequently implicated in hypertrophic cardiomyopathy (HCM). Given the similarity between cMyBPC and MyBPH, we proposed that MyBPH, like cMyBPC, could be involved in HCM pathogenesis and we therefore sought to determine its function. We identified MyBPH-interacting proteins by using yeast two-hybrid (Y2H) analysis.

AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.

Background: Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects.

MT-CYB mutations in hypertrophic cardiomyopathy.

Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT-CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT-CYB mutations might play an important causal or modifying role in HCM.

Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy.

A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity.

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested.

The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study.

Background: The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function.

Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C.

Background: Cardiac contractility is regulated by dynamic phosphorylation of sarcomeric proteins by kinases such as cAMP-activated protein kinase A (PKA). Efficient phosphorylation requires that PKA be anchored close to its targets by A-kinase anchoring proteins (AKAPs). Cardiac Myosin Binding Protein-C (cMyBPC) and cardiac troponin I (cTNI) are hypertrophic cardiomyopathy (HCM)-causing sarcomeric proteins which regulate contractility in response to PKA phosphorylation.

Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population.

Background: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by repeated obsessions and compulsions. Trichotillomania (TTM), a psychiatric disorder characterized by repetitive hairpulling, is presently classified as an impulse control disorder, but has also been viewed as an obsessive-compulsive spectrum disorder. Both conditions are complex disorders, with evidence from family and twin studies indicating that their etiology includes a genetic component.

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure.

Introduction: Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin-angiotensin-aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT(1)R).

Abnormal blood pressure response to exercise occurs more frequently in hypertrophic cardiomyopathy patients with the R92W troponin T mutation than in those with myosin mutations.

Abnormal blood pressure response to exercise is reported to occur in up to a third of hypertrophic cardiomyopathy (HCM) cases and is associated with an increased risk of death, particularly in the young, but it is not known whether the HCM-causing mutation influences blood pressure response to exercise. The purpose of this article is to ascertain whether the blood pressure response to exercise differs among carriers of the R92W mutation in the cardiac troponin T gene (TNNT2), which has been associated with an increased risk of sudden cardiac death in young males; carriers of mutations in the cardiac beta-myosin heavy chain gene (MYH7); and their noncarrier relatives. Thirty R92W(TNNT2) carriers, 51 MYH7 mutation carriers, and 68 of their noncarrier relatives were subjected to bicycle ergonometric exercise testing to assess blood pressure response to, as well as heart rate recovery after, exercise.

Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa.

Little is known about arrhythmogenic right ventricular cardiomyopathy (ARVC) in Africa. The objective of this study was to delineate the clinical characteristics, survival, and genetics of ARVC in South Africa. Information on clinical presentation, electrocardiographic and cardiac imaging findings, histology, and outcome of cases with suspected ARVC was collected using the standardised form of the ARVC Registry of South Africa.

The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive-compulsive disorder (OCD).

Evidence suggests that the Val66Met variant of the brain-derived neurotrophic factor (BDNF) gene may play a role in the etiology of Obsessive-Compulsive Disorder (OCD). In this study, the role of the BDNF Val66Met variant in the etiology and the phenotypic expression of OCD is investigated. Associations between the BDNF Val66Met variant and OCD, obsessive-compulsive symptom dimensions, Yale-Brown Obsessive Compulsive Scale (YBOCS) severity scores, age of onset and family history of obsessive-compulsive symptoms were assessed.

RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1.

RBBP6 (retinoblastoma binding protein 6) is a 250-kDa multifunctional protein that interacts with both p53 and pRb and has been implicated in mRNA processing. It has also been identified as a putative E3 ubiquitin ligase due to the presence of a RING finger domain, although no substrate has been identified up to now. Using the RING finger domain as bait in a yeast two-hybrid screen, we identified YB-1 (Y-box binding protein 1) as a binding partner of RBBP6, localising the interaction to the last 62 residues of YB-1.

Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy, a common, inherited cardiac muscle disease, is primarily caused by mutations in sarcomeric protein-encoding genes and is characterized by overgrowth of ventricular muscle that is highly variable in extent and location. This variability has been partially attributed to locus and allelic heterogeneity of the disease-causing gene, but other factors, including unknown genetic factors, also modulate the extent of hypertrophy that develops in response to the defective sarcomeric functioning. Components of the renin-angiotensin-aldosterone system are plausible candidate hypertrophy modifiers because of their role in controlling blood pressure and biological effects on cardiomyocyte hypertrophy.

Cluster analysis of obsessive-compulsive symptomatology: identifying obsessive-compulsive disorder subtypes.

Background: There is increasing evidence that obsessive-compulsive disorder (OCD) is a heterogeneous disorder. Different clinical subtypes may be characterized by differing pathophysiological mechanisms and treatment outcomes.

Methods: A cluster analysis was performed on 45 items of the Yale-Brown Obsessive-Compulsive Symptoms Checklist (YBOCS-CL) for 261 patients with OCD.

Troponin T and beta-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy.

Aims: The validity of genotype:phenotype correlation studies in human hypertrophic cardiomyopathy (HCM) has recently been questioned, yet animal models and in vitro studies suggest distinct effects for different mutations. The aims of this study were to investigate whether distinct HCM-mutations have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy.

Methods And Results: Individuals aged 20-65 belonging to 21 R92W(TNNT2), R403W(MYH7), or A797T(MYH7) mutation-bearing families were investigated with 2D, M-mode, and Doppler echocardiography.

Investigating the possible effects of trauma experiences and 5-HTT on the dissociative experiences of patients with OCD using path analysis and multiple regression.

Dissociation is defined as the disruption of the usually integrated functions of consciousness, such as memory, identity, and perceptions of the environment. Causes include various psychological, neurological and neurobiological mechanisms, none of which have been consistently supported. To our knowledge, the role of gene-environment interactions in dissociative experiences in obsessive-compulsive disorder (OCD) has not previously been investigated.

Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD).

Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case-control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors.

Long-term follow-up of R403WMYH7 and R92WTNNT2 HCM families: mutations determine left ventricular dimensions but not wall thickness during disease progression.

Background: The clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s).

Genetic correlates in trichotillomania--A case-control association study in the South African Caucasian population.

Background: Trichotillomania (TTM), a prevalent and disabling psychiatric disorder characterized by repetitive hair-pulling, is presently classified as an impulse control disorder (ICD). Some have argued, however, that TTM is an obsessive-compulsive spectrum disorder (OCSD). There is some evidence that both disorders (OCD and TTM) are mediated by serotonergic (5-HT) and dopaminergic pathways.

Hoarding in obsessive-compulsive disorder: clinical and genetic correlates.

Objective: Hoarding may be an important symptom dimension in obsessive-compulsive disorder (OCD). Hoarding in OCD has been associated with poor insight, poorer response to selective serotonin reuptake inhibitors than other OCD symptom dimensions, and a distinctive psychobiological profile. The clinical and genetic correlates of hoarding in OCD therefore deserve additional investigation.

Early- versus late-onset obsessive-compulsive disorder: investigating genetic and clinical correlates.

There is increasing evidence that obsessive-compulsive disorder (OCD) is mediated by genetic factors. Although the precise mechanism of inheritance is unclear, recent evidence has pointed towards the involvement of the serotonergic and dopaminergic systems in the disorder's development. Furthermore, early-onset OCD appears to be a subtype that exhibits distinct clinical features and that is associated with greater familial loading.