Recurrent intrauterine fetal loss due to near absence of HERG: Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation

Zahurul A. Bhuiyan, Tarek S. Momenah, Qiuming Gong, Ahmad S. Amin, Saleh Al Ghamdi, Julene S. Carvalho, Tessa Homfray, Marcel M A M Mannens, Zhengfeng Zhou, Arthur A M Wilde

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    Abstract

    Background: Inherited arrhythmias may underlie intrauterine and neonatal arrhythmias. Resolving the molecular genetic nature of these rare cases provides significant insight into the role of the affected proteins in arrhythmogenesis and (extra-) cardiac development. Objective: The purpose of this study was to perform clinical, molecular, and functional studies of a consanguineous Arabian family with repeated early miscarriages and two intrauterine fetal losses in the early part of the third trimester of pregnancy due to persistent arrhythmias. Methods: In-depth clinical investigation was performed in two siblings, both of whom developed severe arrhythmia during the second trimester of pregnancy. Homozygosity mapping with microsatellite repeat polymorphic markers encompassing various cardiac ion channel genes linked to electrical instability of the heart was performed. Screening of the candidate gene in the homozygous locus was performed. Biochemical and electrophysiologic analysis was performed to elucidate the function of the mutated gene. Results: Screening of the HERG gene in the homozygous locus detected a homozygous nonsense mutation Q1070X in the HERG C-terminus in affected children. Biochemical and functional analysis of the Q1070X mutant showed that although the mutant HERG had the ability to traffic to the plasma membrane and to form functional channels, it was destroyed by the nonsense-mediated decay (NMD) pathway before its translation. NMD leads to near absence of HERG in homozygous Q1070X mutation carriers, causing debilitating arrhythmias (prior to birth) in homozygous carriers but no apparent phenotype in heterozygous carriers. Conclusion: Homozygous HERG Q1070X is equivalent to near functional knockout of HERG. Clinical consequences appear early, originating during the early stages of embryonic life. The NMD pathway renders HERG Q1070X functionless before it can form a functional ion channel.

    Original languageEnglish (US)
    Pages (from-to)553-561
    Number of pages9
    JournalHeart Rhythm
    Volume5
    Issue number4
    DOIs
    StatePublished - Apr 2008

    Fingerprint

    Cardiac Arrhythmias
    Mutation
    Ion Channels
    Genes
    Aptitude
    Nonsense Codon
    Third Pregnancy Trimester
    Second Pregnancy Trimester
    Spontaneous Abortion
    Microsatellite Repeats
    Siblings
    Molecular Biology
    Cell Membrane
    Parturition
    Phenotype
    Proteins

    Keywords

    • Electrophysiology
    • HERG
    • Long QT syndrome
    • Nonsense-mediated decay
    • Sudden cardiac death

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Recurrent intrauterine fetal loss due to near absence of HERG : Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. / Bhuiyan, Zahurul A.; Momenah, Tarek S.; Gong, Qiuming; Amin, Ahmad S.; Ghamdi, Saleh Al; Carvalho, Julene S.; Homfray, Tessa; Mannens, Marcel M A M; Zhou, Zhengfeng; Wilde, Arthur A M.

    In: Heart Rhythm, Vol. 5, No. 4, 04.2008, p. 553-561.

    Research output: Contribution to journalArticle

    Bhuiyan, Zahurul A. ; Momenah, Tarek S. ; Gong, Qiuming ; Amin, Ahmad S. ; Ghamdi, Saleh Al ; Carvalho, Julene S. ; Homfray, Tessa ; Mannens, Marcel M A M ; Zhou, Zhengfeng ; Wilde, Arthur A M. / Recurrent intrauterine fetal loss due to near absence of HERG : Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. In: Heart Rhythm. 2008 ; Vol. 5, No. 4. pp. 553-561.
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    abstract = "Background: Inherited arrhythmias may underlie intrauterine and neonatal arrhythmias. Resolving the molecular genetic nature of these rare cases provides significant insight into the role of the affected proteins in arrhythmogenesis and (extra-) cardiac development. Objective: The purpose of this study was to perform clinical, molecular, and functional studies of a consanguineous Arabian family with repeated early miscarriages and two intrauterine fetal losses in the early part of the third trimester of pregnancy due to persistent arrhythmias. Methods: In-depth clinical investigation was performed in two siblings, both of whom developed severe arrhythmia during the second trimester of pregnancy. Homozygosity mapping with microsatellite repeat polymorphic markers encompassing various cardiac ion channel genes linked to electrical instability of the heart was performed. Screening of the candidate gene in the homozygous locus was performed. Biochemical and electrophysiologic analysis was performed to elucidate the function of the mutated gene. Results: Screening of the HERG gene in the homozygous locus detected a homozygous nonsense mutation Q1070X in the HERG C-terminus in affected children. Biochemical and functional analysis of the Q1070X mutant showed that although the mutant HERG had the ability to traffic to the plasma membrane and to form functional channels, it was destroyed by the nonsense-mediated decay (NMD) pathway before its translation. NMD leads to near absence of HERG in homozygous Q1070X mutation carriers, causing debilitating arrhythmias (prior to birth) in homozygous carriers but no apparent phenotype in heterozygous carriers. Conclusion: Homozygous HERG Q1070X is equivalent to near functional knockout of HERG. Clinical consequences appear early, originating during the early stages of embryonic life. The NMD pathway renders HERG Q1070X functionless before it can form a functional ion channel.",
    keywords = "Electrophysiology, HERG, Long QT syndrome, Nonsense-mediated decay, Sudden cardiac death",
    author = "Bhuiyan, {Zahurul A.} and Momenah, {Tarek S.} and Qiuming Gong and Amin, {Ahmad S.} and Ghamdi, {Saleh Al} and Carvalho, {Julene S.} and Tessa Homfray and Mannens, {Marcel M A M} and Zhengfeng Zhou and Wilde, {Arthur A M}",
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    T1 - Recurrent intrauterine fetal loss due to near absence of HERG

    T2 - Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation

    AU - Bhuiyan, Zahurul A.

    AU - Momenah, Tarek S.

    AU - Gong, Qiuming

    AU - Amin, Ahmad S.

    AU - Ghamdi, Saleh Al

    AU - Carvalho, Julene S.

    AU - Homfray, Tessa

    AU - Mannens, Marcel M A M

    AU - Zhou, Zhengfeng

    AU - Wilde, Arthur A M

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    N2 - Background: Inherited arrhythmias may underlie intrauterine and neonatal arrhythmias. Resolving the molecular genetic nature of these rare cases provides significant insight into the role of the affected proteins in arrhythmogenesis and (extra-) cardiac development. Objective: The purpose of this study was to perform clinical, molecular, and functional studies of a consanguineous Arabian family with repeated early miscarriages and two intrauterine fetal losses in the early part of the third trimester of pregnancy due to persistent arrhythmias. Methods: In-depth clinical investigation was performed in two siblings, both of whom developed severe arrhythmia during the second trimester of pregnancy. Homozygosity mapping with microsatellite repeat polymorphic markers encompassing various cardiac ion channel genes linked to electrical instability of the heart was performed. Screening of the candidate gene in the homozygous locus was performed. Biochemical and electrophysiologic analysis was performed to elucidate the function of the mutated gene. Results: Screening of the HERG gene in the homozygous locus detected a homozygous nonsense mutation Q1070X in the HERG C-terminus in affected children. Biochemical and functional analysis of the Q1070X mutant showed that although the mutant HERG had the ability to traffic to the plasma membrane and to form functional channels, it was destroyed by the nonsense-mediated decay (NMD) pathway before its translation. NMD leads to near absence of HERG in homozygous Q1070X mutation carriers, causing debilitating arrhythmias (prior to birth) in homozygous carriers but no apparent phenotype in heterozygous carriers. Conclusion: Homozygous HERG Q1070X is equivalent to near functional knockout of HERG. Clinical consequences appear early, originating during the early stages of embryonic life. The NMD pathway renders HERG Q1070X functionless before it can form a functional ion channel.

    AB - Background: Inherited arrhythmias may underlie intrauterine and neonatal arrhythmias. Resolving the molecular genetic nature of these rare cases provides significant insight into the role of the affected proteins in arrhythmogenesis and (extra-) cardiac development. Objective: The purpose of this study was to perform clinical, molecular, and functional studies of a consanguineous Arabian family with repeated early miscarriages and two intrauterine fetal losses in the early part of the third trimester of pregnancy due to persistent arrhythmias. Methods: In-depth clinical investigation was performed in two siblings, both of whom developed severe arrhythmia during the second trimester of pregnancy. Homozygosity mapping with microsatellite repeat polymorphic markers encompassing various cardiac ion channel genes linked to electrical instability of the heart was performed. Screening of the candidate gene in the homozygous locus was performed. Biochemical and electrophysiologic analysis was performed to elucidate the function of the mutated gene. Results: Screening of the HERG gene in the homozygous locus detected a homozygous nonsense mutation Q1070X in the HERG C-terminus in affected children. Biochemical and functional analysis of the Q1070X mutant showed that although the mutant HERG had the ability to traffic to the plasma membrane and to form functional channels, it was destroyed by the nonsense-mediated decay (NMD) pathway before its translation. NMD leads to near absence of HERG in homozygous Q1070X mutation carriers, causing debilitating arrhythmias (prior to birth) in homozygous carriers but no apparent phenotype in heterozygous carriers. Conclusion: Homozygous HERG Q1070X is equivalent to near functional knockout of HERG. Clinical consequences appear early, originating during the early stages of embryonic life. The NMD pathway renders HERG Q1070X functionless before it can form a functional ion channel.

    KW - Electrophysiology

    KW - HERG

    KW - Long QT syndrome

    KW - Nonsense-mediated decay

    KW - Sudden cardiac death

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