Browsing by Author "Moolman-Smook, Johanna C."
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- ItemThe KCNE genes in hypertrophic cardiomyopathy : a candidate gene study(BioMed Central, 2011-10) Hedley, Paula L.; Havndrup, Ole; Andersen, Paal S.; Aidt, Frederik H.; Jensen, Morten; Moolman-Smook, Johanna C.; Bundgaard, Henning; Christiansen, MichaelAbstract 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. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic disease associated with an improper hypertrophic response. Results The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmia
- ItemLong-term follow-up of R403W MYH7 and R92W TNNT2 HCM families : mutations determine left ventricular dimensions but not wall thickness during disease progression(Clinics Cardiv Publishing, 2007-06) Revera, Miriam; Van der Merwe, Lize; Heradien, Marshall; Goosen, Althea; Corfield, Valerie A.; Brink, Paul A.; Moolman-Smook, Johanna C.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). Methods: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92WTNNT2 and R403WMYH7, both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92WTNNT2 and R403WMYH7 mutation carriers in these and additional South African R92WTNNT2 families after a mean 11.08 ± 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. Results: We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92WTNNT2 carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403WMYH7 carriers, which may require clinical follow-up over the longer term. Conclusions: Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly genderassociated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.
- ItemMolecular genetics of cardiomyopathy: changing times, shifting paradigms(Clinics Cardiv Publishing, 2003-06) Moolman-Smook, Johanna C.; Mayosi, Bongani M.; Brink, Paul A.; Corfield, Valerie 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.
- ItemMyomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C(BioMed Central, 2011-05) Uys, Gerrida M.; Ramburan, Amsha; Loos, Benjamin; Kinnear, Craig J.; Korkie, Lundi J.; Mouton, Jomien; Riedemann, Johann; Moolman-Smook, Johanna C.Abstract. 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. Results During a yeast 2-hybrid (Y2H) library screen using a trisphosphorylation mimic of the C1-C2 region of cMyBPC, we identified isoform 4 of myomegalin (MMGL) as an interactor of this N-terminal cMyBPC region. As MMGL has previously been shown to interact with phosphodiesterase 4D, we speculated that it may be a PKA-anchoring protein (AKAP). To investigate this possibility, we assessed the ability of MMGL isoform 4 to interact with PKA regulatory subunits R1A and R2A using Y2H-based direct protein-protein interaction assays. Additionally, to further elucidate the function of MMGL, we used it as bait to screen a cardiac cDNA library. Other PKA targets, viz. CARP, COMMD4, ENO1, ENO3 and cTNI were identified as putative interactors, with cTNI being the most frequent interactor. We further assessed and confirmed these interactions by fluorescent 3D-co-localization in differentiated H9C2 cells as well as by in vivo co-immunoprecipitation. We also showed that quantitatively more interaction occurs between MMGL and cTNI under β-adrenergic stress. Moreover, siRNA-mediated knockdown of MMGL leads to reduction of cMyBPC levels under conditions of adrenergic stress, indicating that MMGL-assisted phosphorylation is requisite for protection of cMyBPC against proteolytic cleavage. Conclusions This study ascribes a novel function to MMGL isoform 4: it meets all criteria for classification as an AKAP, and we show that is involved in the phosphorylation of cMyBPC as well as cTNI, hence MMGL is an important regulator of cardiac contractility. This has further implications for understanding the patho-aetiology of HCM-causing mutations in the genes encoding cMyBPC and cTNI, and raises the question of whether MMGL might itself be considered a candidate HCM-causing or modifying factor.