Browsing by Author "Moolman-Smook J.C."
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- ItemA novel myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity(2012) Andersen P.S.; Hedley P.L.; Page S.P.; Syrris P.; Moolman-Smook J.C.; McKenna W.J.; Elliott P.M.; Christiansen M.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. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT21mm), a resting left ventricular outflow gradient of 36mmHg, and left atrial dilation (54mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion, MYL3 mutations can present with low expressivity and late onset. © Copyright 2012 Paal Skytt Andersen et al.
- ItemGenetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure(2011) Carstens N.; Van Der Merwe L.; Revera M.; Heradien M.; Goosen A.; Brink P.A.; Moolman-Smook J.C.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 (AT1R). However, Ang II binding to Ang II type 2 receptors (AT2R) also has hypertrophy-modulating effects. Methods. We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT2R gene (AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate. Results. We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ∼0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates (p = 0.020). Conclusion. This study therefore confirms a hypertrophy-modulating effect for AT2R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM. © 2010 The Author(s).
- ItemGenetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy(2008) van der Merwe L.; Cloete R.; Revera M.; Heradien M.; Goosen A.; Corfield V.A.; Brink P.A.; Moolman-Smook J.C.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. © The Author(s) 2008.
- ItemHoarding in obsessive-compulsive disorder: Clinical and genetic correlates(2005) Lochner C.; Kinnear C.J.; Hemmings, Sian M. J.; Seller C.; Niehaus D.J.H.; Knowles J.A.; Daniels W.; Moolman-Smook J.C.; Seedat S.; Stein D.J.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. Method: Adult OCD patients (N = 315) underwent a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV Axis I Disorders (Patient Edition) and for Diagnosis of Obsessive-Compulsive Spectrum Disorders. DNA extracted from venous blood (10-30 mL) in a Caucasian subset of the interviewed OCD patients (N = 204) and Caucasian controls (N = 169), including patients (N = 94) and controls (N = 138) of Afrikaner descent, was genotyped to investigate polymorphisms in genes involved in monoamine function and previously hypothesized to be relevant to OCD. Data were collected from 1998 through 2004. Results: OCD patients with hoarding made up 18.1% of the total sample. Compared with nonhoarding OCD, OCD with hoarding was associated with a number of comorbid Axis I disorders, obsessive-compulsive personality disorder, significantly higher OCD severity scores, and more functional impairment. In subjects of Afrikaner descent, the L/L genotype of the COMT Val158Met polymorphism was significantly more common in the OCD hoarding group, with a preponderance of low activity alleles, compared with nonhoarding patients and controls. Conclusions: These data are consistent with the hypothesis that hoarding represents a unique symptom subtype in OCD with a distinctive clinical and psychobiological profile. Further work is needed to determine the psychobiological mechanisms responsible for hoarding and to replicate the genetic findings noted here.
- ItemIdentification of a new missense mutation in MyBP-C associated with hypertrophie cardiomyopathy(1998) Moolman-Smook J.C.; Mayosi B.; Brink P.; Corfield V.A.Hypertrophie cardiomyopathy is a primary cardiac disease, characterised by idiopathic myocardial hypertrophy, and is caused by defects in s arc orner ic protein encoding genes. One of these genes is cardiac myosin binding protein C (MyBP-C), in which a number of splice site and duplication mutations causing HCM have been described. During mutation screening of a South African HCM population by PCR-SSCP, a missense mutation, Arg654His, was detected in one proband. Although the mutation was present in his three adult children, only the proband himself was markedly affected. This is the first report of a disease associated missense mutation hi MyBP-C which does not affect the myosin or titin binding domains.
- ItemMolecular genetics of cardiomyopathy: Changing times, shifting paradigms(2003) Moolman-Smook J.C.; Mayosi B.M.; Brink P.A.; Corfield V.A.Congestive heart failure is a major problem in developed and developing countries alike. Primary dysfunction of the heart muscle accounts for a significant proportion of patients with a non-ischaemic cause of heart failure. Application of genetic techniques has facilitated identification of some molecular causes of the inherited form of these diseases, dramatically increasing our understanding of the pathogenesis of these primary, previously termed 'idiopathic', cardiomyopathies over the last few decades. Knowledge of the different causes is beginning to coalesce into aetiological principles underlying the clinically distinguished cardiomyopathies. Hypertrophic cardiomyopathy (HCM) now appears to be a disease caused by a dysfunctional sarcomere, dilated cardiomyopathy (DCM), a disease of myocytic structural instability, and arrhythmogenic right ventricular cardiomyopathy, a disease of accelerated myocyte death. The aetiology of both HCM and DCM probably also involves cardiac energy imbalances, while additional factors modify the clinical expression in all cardiomyopathies. Even though our knowledge of the genetic aetiology of the cardiomyopathies is still incomplete, it already has relevant clinical significance. Elucidation of the full genetic contribution to the development and progression of the cardiomyopathies represents a new challenge in the study of these diseases, and will undoubtedly lead to new therapeutic approaches in the not-too-distant future.
- ItemMutations of the light meromyosin domain of the β-myosin heavy chain rod in hypertrophic cardiomyopathy(2002) Blair E.; Redwood C.; De Jesus Oliveira M.; Moolman-Smook J.C.; Brink P.; Corfield V.A.; Ostman-Smith I.; Watkins H.Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is β-myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with another disease-causing mutation. The position of this residue within the LMM region of myosin suggests that it may be important for thick filament assembly or for accessory protein binding. A further missense mutation in exon 37, Ser1776Gly, segregated with disease in a single family and was absent from 400 population-matched control chromosomes. Because the Ser1776 residue occupies a core position in the myosin rod at which the substitution of glycine is extremely energetically unfavorable, it is likely to disrupt the coiled-coil structure. We conclude that mutation of the LMM can cause HCM and that such mutations may act through novel mechanisms of disease pathogenesis involving myosin filament assembly or interaction with thick filament binding proteins.
- ItemThe KCNE genes in hypertrophic cardiomyopathy: A candidate gene study(2011) Hedley P.L.; Haundrup O.; Andersen P.S.; Aidt F.H.; Jensen M.; Moolman-Smook J.C.; Bundgaard H.; Christiansen M.
- ItemThe origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: A unique profile of both independent and founder events(1999) Moolman-Smook J.C.; De Lange W.J.; Bruwer E.C.D.; Brink P.A.; Corfield V.A.Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two south African subpopulations, one of mixed ancestry and one of northern- European descent. Previously, we had detected three novel mutations - Ala797Thr in the β-myosin heavy-chain gene (βMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC) - and two documented βMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations - Gln499Lys in βMHC and Va1896Met and Δc756 in MyBPC - and the documented βMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the βMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the βMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.