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Mechanistic insight into an exonic splice defect mutation from native induced pluripotent stem cell-derived cardiomyocytes

  • Zahurul A. Bhuiyan
    Correspondence
    Address reprint requests and correspondence: Dr Zahurul A. Bhuiyan, Laboratoire de Génétique, Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, BH19-707, 1011 Lausanne, VD, Switzerland.
    Affiliations
    Laboratoire de Génétique, Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    Search for articles by this author
      Long QT syndrome (LQTS)–associated mutations are predominantly found in cardiac genes that are responsible for synchronous action potential generation.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      Depolarization begins with the opening of the voltage-gated sodium channel (INa) channel for the rapid passage of Na+ into cardiomyocytes (CMs).
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      The SCN5A gene encodes for the α subunit of this INa channel.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      Depolarization is followed by repolarization, where outward potassium currents rapidly activating delayed rectifier potassium channel (IKr) and slowly activating delayed rectifier potassium channel (IKs) are the major currents.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      IKr is composed of KCNH2 encoding Kv11.1/HERG (α subunit) along with its β-subunit MiRP1 encoded by the KCNE2 gene.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      IKs is made of the KCNQ1 gene encoding Kv7.1/KvLQT1 (α subunit) along with its β-subunit Mink encoded by the KCNE1 gene.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      A mutation in SCN5A that causes sustained opening of the INa channel is a causal factor in LQTS type 3.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      Conversely, diminution or loss of function of IKr or IKs channels is the abnormality behind LQTS type 2 and type 1, respectively, because of mutations in KCNH2 and KCNQ1 genes.
      • Bhuiyan Z.A.
      • Al-Shahrani S.
      • Al-Aama J.
      • Wilde A.A.
      • Momenah T.S.
      Congenital long QT syndrome: an update and present perspective in Saudi Arabia.
      The Kv7.1/KvLQT1 protein consists of 676 amino acids (aa) divided into the following: N terminus: 1–124 aa; 6 membrane-spanning segments: 124–170 aa (S1-S2), 196–241 aa (S3-S4), and 263–355 aa (S5-S6); 2 connecting cytoplasmic loops (C loops): 171–195 aa (S2-S3 linker) and 242–262 aa (S4-S5 linker); and an intracellular C-terminus region (355–676 aa).
      • Moss A.J.
      • Shimizu W.
      • Wilde A.A.
      • et al.
      Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.
      IKs has an important role in β-adrenergic receptor stimulation.
      • Heijman J.
      • Spätjens R.L.
      • Seyen S.R.
      • Lentink V.
      • Kuijpers H.J.
      • Boulet I.R.
      • de Windt L.J.
      • David M.
      • Volders P.G.
      Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.
      β-Adrenergic drive leads to accumulation of cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA).
      • Heijman J.
      • Spätjens R.L.
      • Seyen S.R.
      • Lentink V.
      • Kuijpers H.J.
      • Boulet I.R.
      • de Windt L.J.
      • David M.
      • Volders P.G.
      Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.
      cAMP-dependent PKA is anchored to the IKs channel by the A-kinase anchoring protein Yotiao.
      • Heijman J.
      • Spätjens R.L.
      • Seyen S.R.
      • Lentink V.
      • Kuijpers H.J.
      • Boulet I.R.
      • de Windt L.J.
      • David M.
      • Volders P.G.
      Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.
      The PKA-mediated phosphorylation of Ser27 in the Kv7.1/KvLQT1 protein is a key regulator of IKs.
      • Heijman J.
      • Spätjens R.L.
      • Seyen S.R.
      • Lentink V.
      • Kuijpers H.J.
      • Boulet I.R.
      • de Windt L.J.
      • David M.
      • Volders P.G.
      Dominant-negative control of cAMP-dependent IKs upregulation in human long-QT syndrome type 1.
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