Browsing by Subject "CALMODULIN"

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  • Penttinen, Kirsi; Swan, Heikki; Vanninen, Sari; Paavola, Jere; Lahtinen, Annukka M.; Kontula, Kimmo; Aalto-Setala, Katriina (2015)
    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from sarcoplasmic reticulum. Dantrolene, an inhibitor of sarcoplasmic Ca2+ release, has been shown to rescue this abnormal Ca2+ release in vitro. We assessed the antiarrhythmic efficacy of dantrolene in six patients carrying various RyR2 mutations causing CPVT. The patients underwent exercise stress test before and after dantrolene infusion. Dantrolene reduced the number of premature ventricular complexes (PVCs) on average by 74% (range 33-97) in four patients with N-terminal or central mutations in the cytosolic region of the RyR2 protein, while dantrolene had no effect in two patients with mutations in or near the transmembrane domain. Induced pluripotent stem cells (iPSCs) were generated from all the patients and differentiated into spontaneously beating cardiomyocytes (CMs). The antiarrhythmic effect of dantrolene was studied in CMs after adrenaline stimulation by Ca2+ imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca2+ cycling abnormalities in 80% (range 65-97) of cells while with mutations in or near the transmembrane domain only in 23 or 32% of cells. In conclusion, we demonstrate that dantrolene given intravenously shows antiarrhythmic effects in a portion of CPVT1 patients and that iPSC derived CM models replicate these individual drug responses. These findings illustrate the potential of iPSC models to individualize drug therapy of inherited diseases.
  • Huttunen, Heta; Hero, Matti; Lääperi, Mitja; Känsäkoski, Johanna; Swan, Heikki; Hirsch, Joel A.; Miettinen, Päivi J.; Raivio, Taneli (2018)
    Objective: Two missense mutations in KCNQ1, an imprinted gene that encodes thealpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1) due to loss-of-function mutations in KCNQ1. Design: Medical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed. Methods: Clinical and endocrine data of the LQT1 patients were included in the analyses. Results: At birth, patients with a maternally inherited mutation (n = 52) were shorter than those with paternal inheritance of the mutation (n = 29) (birth length, -0.70 +/- 1.1 SDS vs. -0.2 +/- 1.0 SDS, P <0.05). Further analyses showed, however, that only newborns (n = 19) of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation (n = 29) (-0.89 +/- 1.0 SDS vs. -0.20 +/- 1.0 SDS, P <0.05; and 3,173 +/- 469 vs. 3,515 +/- 466 g, P <0.05). Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels (P = 0.011) and significant catch-up growth during the first year of life (.0.08 SDS/month, P = 0.004). Later, childhood growth of the patients was unremarkable. Conclusion: Loss-of-function mutations in KCNQ1 are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients-a phenomenon followed by catch-up growth after birth.
  • Tommiska, Johanna; Känsäkoski, Johanna; Skibsbye, Lasse; Vaaralahti, Kirsi; Liu, Xiaonan; Lodge, Emily J.; Tang, Chuyi; Yuan, Lei; Fagerholm, Rainer; Kanters, Jorgen K.; Lahermo, Päivi; Kaunisto, Mari; Keski-Filppula, Riikka; Vuoristo, Sanna; Pulli, Kristiina; Ebeling, Tapani; Valanne, Leena; Sankila, Eeva-Marja; Kivirikko, Sirpa; Lääperi, Mitja; Casoni, Filippo; Giacobini, Paolo; Phan-Hug, Franziska; Buki, Tal; Tena-Sempere, Manuel; Pitteloud, Nelly; Veijola, Riitta; Lipsanen-Nyman, Marita; Kaunisto, Kari; Mollard, Patrice; Andoniadou, Cynthia L.; Hirsch, Joel A.; Varjosalo, Markku; Jespersen, Thomas; Raivio, Taneli (2017)
    Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c. 347G>T p.(Arg116Leu) or c. 1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 beta-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.