Browsing by Subject "FOUNDER MUTATIONS"

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  • Tarkiainen, Mika; Sipola, Petri; Jalanko, Mikko; Helio, Tiina; Laine , Mika; Jarvinen, Vesa; Hayrinen, Kaisu; Lauerma, Kirsi; Kuusisto, Johanna (2016)
    Background: Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well as in unselected consecutive patients with HCM, and respective controls. Methods: Anterior mitral valve leaflet (AML) and posterior mitral valve leaflet (PML) lengths were measured by CMR in 47 subjects with the Q1061X mutation in the gene encoding MYBPC3 and in 20 healthy relatives without the mutation. In addition, mitral valve leaflet lengths were measured by CMR in 80 consecutive non-genotyped patients with HCM in CMR and 71 age-and gender-matched healthy subjects. Results: Of the subjects with the MYBPC-Q1016X mutation, 32 had left ventricular hypertrophy (LVH, LV maximal wall thickness >= 13 mm in CMR) and 15 had no hypertrophy. PML was longer in patients with the MYBPC3-Q1061X mutation and LVH than in controls of the MYBPC group (12.8 +/- 2.8 vs 10.6 +/- 1.9 mm, P = 0.013), but the difference between the groups was not statistically significant when PML was indexed for BSA (P = 0.066), or when PML length was adjusted for BSA, age, gender, LV mass and ejection fraction (P = 0.195). There was no significant difference in the PML length in mutation carriers without LVH and controls (11.1 +/- 3.4 vs 10.6 +/- 1.9, P = 0.52). We found no difference in AML lengths between the MYBPC mutation carriers with or without hypertrophy and controls. In 80 consecutive non-genotyped patients with HCM, there was no difference either in AML or PML lengths in subjects with HCM compared to respective control subjects. Conclusions: In subjects with HCM caused by the Q1061X mutation in the MYBPC3 gene, the posterior mitral valve leaflets may be elongated, but mitral valve elongation does not constitute primary phenotypic expression of the disease. Instead, elongated mitral valve leaflets seem to be associated with body size and left ventricular remodeling.
  • Tarkiainen, Mika; Sipola, Petri; Jalanko, Mikko; Heliö, Tiina; Jääskeläinen, Pertti; Kivelä, Kati; Laine, Mika; Lauerma, Kirsi; Kuusisto, Johanna (2019)
    This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM)-causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnetic resonance (CMR) in subjects with the Finnish founder mutation Q1016X in the myosin-binding protein C gene (MYBPC3). Septal convexity was measured in end-diastolic 4-chamber CMR image in 67 study subjects (47 subjects with the MYBPC3-Q1061X mutation and 20 healthy relatives without the mutation). Septal convexity was significantly increased in subjects with the MYBPC3-Q1061X mutation and LVH (n = 32) compared to controls (11.4 +/- 4.3 vs 2.7 +/- 3.2 mm, P <0.001). In mutation carriers without LVH, there was a trend for increased septal convexity compared to controls (4.9 +/- 2.5 vs 2.7 +/- 3.2 mm, P = 0.074). When indexed for BSA, septal convexity in mutation carriers without LVH was 2.8 +/- 1.4 mm/m(2) and 1.5 +/- 1.6 mm/m(2) in controls (P = 0.036). In all mutation carriers, septal convexity correlated significantly with body surface area, age, maximal LV wall thickness, LV mass, and late gadolinium enhancement. Subjects with the MYBPC3-Q10961X mutation have increased septal convexity irrespective of the presence of LVH. Septal convexity appears to reflect septal remodeling, and could be useful in recognizing LVH negative mutation carriers.
  • Kuusela, Jukka; Kujala, Ville J.; Kiviaho, Anna; Ojala, Marisa; Swan, Heikki; Kontula, Kimmo; Aalto-Setala, Katriina (2016)
    Human induced pluripotent stem cells (hiPSC) have enabled a major step forward in pathophysiologic studies of inherited diseases and may also prove to be valuable in in vitro drug testing. Long QT syndrome (LQTS), characterized by prolonged cardiac repolarization and risk of sudden death, may be inherited or result from adverse drug effects. Using a microelectrode array platform, we investigated the effects of six different drugs on the electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes as well as hiPSC-derived cardiomyocytes from control subjects and from patients with type 1 (LQT1) and type 2 (LQT2) of LQTS. At baseline the repolarization time was significantly longer in LQTS cells compared to controls. Isoprenaline increased the beating rate of all cell lines by 10-73 % but did not show any arrhythmic effects in any cell type. Different QT-interval prolonging drugs caused prolongation of cardiac repolarization by 3-13 % (cisapride), 10-20 % (erythromycin), 8-23 % (sotalol), 16-42 % (quinidine) and 12-27 % (E-4031), but we did not find any systematic differences in sensitivity between the control, LQT1 and LQT2 cell lines. Sotalol, quinidine and E-4031 also caused arrhythmic beats and beating arrests in some cases. In summary, the drug effects on these patient-specific cardiomyocytes appear to recapitulate clinical observations and provide further evidence that these cells can be applied for in vitro drug testing to probe their vulnerability to arrhythmia.
  • FinHCM Study Grp; Jääskeläinen, Pertti; Vangipurapu, Jagadish; Raivo, Joose; Kuulasmaa, Teemu; Helio, Tiina; Aalto-Setala, Katriina; Kaartinen, Maija; Ilveskoski, Erkki; Vanninen, Sari; Hämäläinen, Liisa; Melin, John; Kokkonen, Jorma; Nieminen, Markku S.; Laakso, Markku; Kuusisto, Johanna; Kervinen, Helena; Mustonen, Juha; Juvonen, Jukka; Niemi, Mari; Uusimaa, Paavo; Junttila, Juhani; Kotila, Matti; Pietila, Mikko; Jyrkila, Heini; Mahonen, Ilkka; Vartia, Paula (2019)
    Aims Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 +/- 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P <0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P <0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P <0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.
  • Wesolowska, Karolina; Elovainio, Marko; Koponen, Mikael; Tuiskula, Annukka M.; Hintsanen, Mirka; Keltikangas-Jarvinen, Liisa; Maattanen, Ilmari; Swan, Heikki; Hintsa, Taina (2017)
    We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships. The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, beta-blockers, antidepressants, and social support (OR = 1.09, 95 % CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95 % CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.
  • Lahtinen, Annukka M.; Marjamaa, Annukka; Swan, Heikki; Kontula, Kimmo (2011)
  • Lahti, Anna L.; Kujala, Ville J.; Chapman, Hugh; Koivisto, Ari-Pekka; Pekkanen-Mattila, Mari; Kerkela, Erja; Hyttinen, Jari; Kontula, Kimmo; Swan, Heikki; Conklin, Bruce R.; Yamanaka, Shinya; Silvennoinen, Olli; Aalto-Setala, Katriina (2012)
  • Sokolenko, Anna P.; Savonevich, Elena L.; Ivantsov, Alexandr O.; Raskin, Grigory A.; Kuligina, Ekatherina S.; Gorodnova, Tatiana V.; Preobrazhenskaya, Elena V.; Kleshchov, Maxim A.; Tiurin, Vladislav I.; Mukhina, Marina S.; Kotiv, Khristina B.; Shulga, Andrey V.; Kuznetsov, Sergey G.; Berlev, Igor V.; Imyanitov, Evgeny N. (2017)
    Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.
  • Jorgenrud, Benedicte; Jalanko, Mikko; Helio, Tiina; Jaaskelainen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S.; Laakso, Markku; Hyotylainen, Tuulia; Oresic, Matej; Kuusisto, Johanna (2015)
    Aims Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the meta-bolome to the echocardiographic parameters. Methods and Results 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Conclusions Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.