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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'. One such gene encodes for cardiac troponin I (TNNI3), a sub-unit of the troponin complex involved in the regulation of striated muscle contraction. We hypothesised that mutations in TNNI3 could underlie this particular phenotype, and we therefore screened TNNI3 for mutations in 115 HCM probands. METHODS: Clinical investigation involved examination, echocardiography, chest X-ray and an electrocardiogram of both the index cases and close relatives. The study cohort consisted of 113 South African HCM probands, with and without known founder HCM mutations, and 100 ethnically matched control individuals. Mutation screening of TNNI3 for diseasecausing mutations were performed using high-resolution melt (HRM) analysis. RESULTS: HRM analyses identified three previously described HCM-causing mutations (p.Pro82Ser, p.Arg162Gln, p.Arg170Gln) and a novel exonic variant (p.Leu144His). A previous study involving the same amino acid identified a p.Leu144Gln mutation in a patient presenting with RCM, with clinical features of HCM. We observed the novel p.Leu144His mutation in three siblings with clinical RCM and varying degrees of ventricular hypertrophy. The isolated index case with the de novo p.Arg170Gln mutation presented with a similar phenotype. Both mutations were absent in a healthy control group. CONCLUSION: We have identified a novel disease-causing p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy, often below the typical diagnostic threshold for HCM. Our study provides information regarding TNNI3 mutations underlying RCM in contrast to other causes of a similar presentation, such as constrictive pericarditis or infiltration of cardiac muscle, all with marked right-sided cardiac manifestations. This study therefore highlights the need for extensive mutation screening of genes encoding for sarcomeric proteins, such as TNNI3 to identify the underlying cause of this particular phenotype.
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Cardiomiopatía Hipertrófica Familiar/diagnóstico , Cardiomiopatía Restrictiva/diagnóstico , Mutación/genética , Troponina I/genética , Disfunción Ventricular Derecha/diagnóstico , Adolescente , Adulto , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Restrictiva/genética , Análisis Mutacional de ADN , Disentimientos y Disputas , Resultado Fatal , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo Genético , Riesgo , Sudáfrica , Disfunción Ventricular Derecha/genéticaRESUMEN
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. The role of MyBPH and cMyBPC in cardiac cell contractility was analysed by measuring the planar cell surface area of differentiated H9c2 rat cardiomyocytes in response to ß-adrenergic stress after siRNA knockdown of MyBPH and cMyBPC. Individual knockdown of either protein had no effect on cardiac contractility, while concurrent knockdowns reduced cardiac contractility. These proteins therefore functionally compensate for one another and are critical for cardiac contractility. We further show that both proteins co-localise with the autophagosomal membrane protein LC3, suggesting that both proteins are involved in autophagosomal membrane maturation processes. The results of this study ascribe novel functions to MyBPH, which may contribute to our understanding of its role in the sarcomere. This study provides evidence for a potential role of MyBPH in HCM, which warrants further investigation.
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Proteínas del Citoesqueleto/metabolismo , Contracción Miocárdica/genética , Miocitos Cardíacos/fisiología , Sarcómeros/fisiología , Actinas/metabolismo , Animales , Autofagia/fisiología , Cardiomiopatía Hipertrófica/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Cultivadas , Proteínas del Citoesqueleto/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Contracción Miocárdica/fisiología , Cadenas Pesadas de Miosina/metabolismo , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño , Ratas , Técnicas del Sistema de Dos Híbridos , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
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. METHODS AND RESULTS: Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001). CONCLUSIONS: AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.
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Proteínas de Anclaje a la Quinasa A/genética , Proteínas del Citoesqueleto/genética , Predisposición Genética a la Enfermedad , Síndrome de Romano-Ward/genética , Adolescente , Adulto , Alelos , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Genotipo , Heterocigoto , Humanos , Leucocitos/citología , Masculino , Persona de Mediana Edad , Modelos Genéticos , Mutación , Fenotipo , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Sudáfrica , Adulto JovenRESUMEN
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. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy.
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Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/genética , ADN Mitocondrial/genética , Haplotipos , Adulto , Anciano , Dinamarca/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Genética de Población , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Filogenia , Factores de RiesgoRESUMEN
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. The MT-CYB gene was sequenced from DNA isolated from blood from 91 Danish HCM probands. Nonsynonymous variants were analyzed by bioinformatics, molecular modeling and simulation. Two germline-inherited, putative disease-causing, nonsynonymous variants: m.15024G>A; p.C93Y and m.15482T>C; p.S246P were identified. Modeling showed that the p.C93Y mutation leads to disruption of the tertiary structure of Cytb by helix displacement, interfering with protein-heme interaction. The p.S246P mutation induces a diproline structure, which alters local secondary structure and induces a kink in the protein backbone, interfering with macromolecular interactions. These molecular effects are compatible with a leaky phenotype, that is, limited but progressive mitochondrial dysfunction. In conclusion, we find that rare, putative leaky mtDNA variants in MT-CYB can be identified in a cohort of HCM patients. We propose that further patients with HCM should be examined for mutations in MT-CYB in order to clarify the role of these variants.
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BACKGROUND: The gene family KCNE1-5, which encode modulating ß-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.
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Cardiomiopatía Hipertrófica/genética , Canales de Potasio con Entrada de Voltaje/genética , Regiones no Traducidas 3' , Estudios de Cohortes , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
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 ß-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.
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Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/genética , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ratas , Receptores Adrenérgicos beta/metabolismo , Troponina I/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
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. Results from a recent knockout animal model suggest that SAP90/PSD95-associated protein 3 (SAPAP3) may be involved in the pathophysiology of both disorders. METHODS: Seven polymorphic variants distributed across the gene encoding SAPAP3 were genotyped in South African white OCD (n = 172), TTM (n = 45), and control (n = 153) subjects. Single-locus and haplotype analyses were conducted to determine association between genetic variants and subjects with OCD, TTM, and controls. RESULTS: Although single-locus analysis revealed a significant association between rs11583978 in SAPAP3 and TTM, this association was nonsignificant after correction for multiple testing. In the OCD group, a significant association was observed between earlier age at onset and the A-T-A-T (rs11583978-rs7541937-rs6662980-rs4652867) haplotype compared with the C-G-G-G haplotype. CONCLUSIONS: This study generated preliminary evidence to link SAPAP3 variants to the development of earlier onset OCD. Future studies should concentrate on locating the susceptibility variant(s) by focusing on functional polymorphisms within SAPAP3.
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Proteínas del Tejido Nervioso/genética , Trastorno Obsesivo Compulsivo/genética , Tricotilomanía/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/diagnóstico , Polimorfismo de Nucleótido Simple , Escalas de Valoración Psiquiátrica , Sudáfrica/etnología , Tricotilomanía/diagnóstico , Población Blanca/genética , Población Blanca/psicologíaRESUMEN
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). However, Ang II binding to Ang II type 2 receptors (AT(2)R) 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 AT(2)R 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 AT(2)R 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.
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Presión Sanguínea/genética , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/fisiopatología , Polimorfismo de Nucleótido Simple/genética , Receptor de Angiotensina Tipo 2/genética , Adulto , Cardiomiopatía Hipertrófica/complicaciones , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Ventrículos Cardíacos/patología , Humanos , Hipertrofia Ventricular Izquierda/complicaciones , Masculino , Persona de Mediana Edad , Análisis de Componente PrincipalRESUMEN
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. Genomic DNA was screened for mutations in plakophylin-2 (PKP2) gene. Survival and its predictors were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods, respectively. Fifty unrelated cases who met the diagnostic criteria for ARVC were enrolled between January 2004 and April 2009. Clinical presentation was similar to that reported in other studies. Annual mortality rate was 2.82%, five-year cumulative mortality rate 10%, and mean age at death 36.9 +/- 14.7 years. Overall survival was similar to the general South African population (P = 0.25). Independent risk factors for death were syncope (Hazard Ratio [HR] 10.73, 95% Confidence Interval [CI] 1.88-61.18, P = 0.008) and sustained ventricular tachycardia (HR = 22.97, 95%CI 2.33-226.18, P = 0.007). Seven PKP2 gene mutations were found in 9/36 (25%) unrelated participants, five being novel. The novel C1162T mutation occurred in four white South Africans sharing a common haplotype, suggesting a founder effect. Compound heterozygotes exhibited a severe phenotype signifying an allele dose effect. ARVC is associated with early mortality that is no different to the general South Africa population whose lifespan is shortened by HIV/AIDS. PKP2 gene mutations are common, have an allele dose effect, and a novel founder effect in white South Africans.
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Displasia Ventricular Derecha Arritmogénica/genética , Mutación , Placofilinas/genética , Adulto , Edad de Inicio , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/etnología , Displasia Ventricular Derecha Arritmogénica/mortalidad , Femenino , Efecto Fundador , Genotipo , Haplotipos , Humanos , Masculino , Polimorfismo Genético , Grupos Raciales/genética , Sistema de Registros , Sudáfrica/epidemiología , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
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. Additional echocardiographic and demographic details were documented for all participants. R92W(TNNT2) carriers demonstrated significantly more abnormal blood pressure responses to exercise (P = .021; odds ratio 3.03; confidence interval 1.13-8.12) and smaller increases in systolic blood pressure than MYH7 mutation carriers or related noncarrier control individuals. Although abnormal blood pressure response occurred at similar frequencies in males in all groups (23%-26%), the percentage of R92W(TNNT2) females with abnormal blood pressure response was 64%, compared with 25% for MYH7 and 22% for noncarriers. Therefore, these results show that blood pressure response to exercise is influenced by genotype and gender in patients with HCM.
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Presión Sanguínea , Miosinas Cardíacas/genética , Cardiomiopatía Hipertrófica/genética , Prueba de Esfuerzo , Mutación , Troponina T/genética , Adolescente , Adulto , Anciano , Presión Sanguínea/genética , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/fisiopatología , Muerte Súbita Cardíaca/etiología , Ecocardiografía , Femenino , Frecuencia Cardíaca , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
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. The BDNF Val66Met variant was genotyped in 419 patients with sub-/clinical OCD and 650 controls. No differences in allele or genotype frequency were observed between cases and controls. In females with OCD, the Met66Met genotype was associated with later age of onset and a trend for a negative family history, whereas the Val66Val genotype was associated with a trend for lower YBOCS severity scores. Item-level factor analysis revealed six factors: 1) Contamination/cleaning; 2) Aggressive obsessions/checking; 3) Symmetry obsessions, counting, ordering and repeating; 4) Sexual/religious obsessions; 5) Hoarding and 6) Somatic obsessions/checking. A trend was found for a positive association between Factor 4 (Sexual/religious obsessions) and the BDNF Val66Val genotype. The results suggest that BDNF function may be implicated in the mediation of OCD. We found that for the BDNF Met66Met genotype may be associated with a milder phenotype in females and a possible role for the BDNF Val66Val genotype and the BDNF Val66 allele in the sexual/religious obsessions.
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Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Asociación Genética , Mutación Missense , Trastorno Obsesivo Compulsivo/genética , Adulto , Edad de Inicio , Estudios de Casos y Controles , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Factores Sexuales , Adulto JovenRESUMEN
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. We showed, furthermore, that both full-length RBBP6 and the isolated RING finger domain were able to ubiquitinate YB-1, resulting in its degradation in the proteosome. As a result, RBBP6 was able to suppress the levels of YB-1 in vivo and to reduce its transactivational ability. In the light of the important role that YB-1 appears to play in tumourigenesis, our results suggest that RBBP6 may be a relevant target for therapeutic drugs aimed at modifying the activity of YB-1.
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Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Dominios y Motivos de Interacción de Proteínas , Mapeo de Interacción de Proteínas , Dominios RING Finger , Proteínas Portadoras/química , Línea Celular , Proteínas de Unión al ADN/química , Humanos , Proteínas Nucleares/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Técnicas del Sistema de Dos Híbridos , Ubiquitina-Proteína Ligasas , Ubiquitinación , Proteína 1 de Unión a la Caja YRESUMEN
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.
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Cardiomiopatía Hipertrófica/genética , Variación Genética , Hipertrofia Ventricular Izquierda/patología , Peptidil-Dipeptidasa A/genética , Adulto , Enzima Convertidora de Angiotensina 2 , Cardiomiopatía Hipertrófica/patología , Estudios de Cohortes , Familia , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/genética , Polimorfismo de Nucleótido Simple , Caracteres SexualesRESUMEN
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. Cardiac structural and functional parameters were compared between prehypertrophic mutation-carriers and their non-carrier family members, with concomitant adjustment for appropriate covariates. Findings were evaluated against existing animal and in vitro functional data. The distinct functional effect of the R92W(TNNT) mutation was a relative increase in systolic functional parameters, that of the A797T(MYH7) mutation was reduced diastolic function, while the R403W(MYH7) mutation reduced both systolic and diastolic function. The observed early effects of the R92W(TNNT2) mutation mechanistically fit with prolonged force-transients precipitated by increased Ca(2+) sensitivity of the thin filament, and that of the MYH7 mutations with local ATP depletion. CONCLUSION: Evaluation of the impact of the mutations on cardiac structure and function in prehypertrophic mutation-carriers, relative to the baseline norm provided by their non-carrier family members, best recapitulated existing animal and in vitro functional data, while inclusion of mutation-carriers with hypertrophy obscured such findings. The results prompt speculation that timely treatment aimed at ameliorating Ca(2+) sensitivity for R92W(TNNT2)-carriers, and energy depletion for MYH7 mutation-carriers, may offer a plausible approach for preventing progression from a preclinical into a decompensated state.
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Miosinas Cardíacas/genética , Cardiomiopatía Hipertrófica/genética , Mutación , Contracción Miocárdica/genética , Cadenas Pesadas de Miosina/genética , Troponina T/genética , Función Ventricular Izquierda/genética , Adenosina Trifosfato/metabolismo , Adulto , Animales , Señalización del Calcio , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/fisiopatología , Ecocardiografía Doppler , Femenino , Genotipo , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Miocardio/metabolismo , Miocardio/patología , FenotipoRESUMEN
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. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/fisiología , Variación Genética/genética , Trastorno Obsesivo Compulsivo/genética , Adulto , Factor Neurotrófico Derivado del Encéfalo/genética , Aberraciones Cromosómicas , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/etnología , Vigilancia de la Población , Sudáfrica , Encuestas y CuestionariosRESUMEN
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. Cluster solutions emerging at different linkage distance levels, and the associations of identified clusters with demographic, clinical and relevant genetic variables, were investigated. RESULTS: A 6-cluster solution emerged at a linkage distance level of 1.5, and a 3-cluster solution emerged at a linkage distance level of 2.1. The 3 clusters in the latter solution were labeled I) Contamination / washing, II) Hoarding / symmetry / ordering, and III) Obsessional / checking. Increased Cluster III scores were associated with earlier age of OCD onset and the Met/Met (L/L) genotype of the COMT Val158Met polymorphism. CONCLUSION: The data here are consistent with previous work delineating the different symptom subtypes of OCD, also with previous work suggesting that the Met/Met (L/L) genotype of the COMT Val158Met polymorphism may be associated with anxiety symptoms, as well as with previous work suggesting that dopaminergic genes may be particularly important in early-onset OCD.
Asunto(s)
Catecol O-Metiltransferasa/genética , Trastorno Obsesivo Compulsivo/clasificación , Trastorno Obsesivo Compulsivo/psicología , Adolescente , Adulto , Anciano , Análisis de Varianza , Análisis por Conglomerados , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
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. Eighty-three Caucasian patients (29 male, 54 female) with a principal diagnosis of OCD were included. The Dissociative Experiences Scale was used to assess dissociation. The role of childhood trauma (assessed with the Childhood Trauma Questionnaire), and a functional 44-bp insertion/deletion polymorphism in the promoter region of the serotonin transporter, or 5-HTT, in mediating dissociation, was investigated using multiple regression analysis and path analysis using the partial least squares model. Both analyses indicated that an interaction between physical neglect and the S/S genotype of the 5-HTT gene significantly predicted dissociation in patients with OCD. Dissociation may be a predictor of poorer treatment outcome in patients with OCD; therefore, a better understanding of the mechanisms that underlie this phenomenon may be useful. Here, two different but related statistical techniques (multiple regression and partial least squares), confirmed that physical neglect and the 5-HTT genotype jointly play a role in predicting dissociation in OCD.
Asunto(s)
Trastornos Disociativos/metabolismo , Trastorno Obsesivo Compulsivo/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Adulto , Comorbilidad , Interpretación Estadística de Datos , Demografía , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Análisis de Regresión , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/genética , Encuestas y CuestionariosRESUMEN
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). METHODS: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92W(TNNT2) and R403W(MYH7), both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92W(TNNT2) and R403W(MYH7) mutation carriers in these and additional South African R92W(TNNT2) 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 R92W(TNNT2) 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 R403W(MYH7) 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 gender-associated 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.