Paradigm of genetic mosaicism and lone atrial fibrillation: Physiological characterization of a connexin 43-deletion mutant identified from atrial tissue

Isabelle L. Thibodeau, Ji Xu, Qiuju Li, Gele Liu, Khanh Lam, John P. Veinot, David H. Birnie, Douglas L. Jones, Andrew D. Krahn, Robert Lemery, Bruce J Nicholson, Michael H. Gollob

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF. Methods and results: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins. Conclusions: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.

Original languageEnglish (US)
Pages (from-to)236-244
Number of pages9
JournalCirculation
Volume122
Issue number3
DOIs
StatePublished - Jul 20 2010
Externally publishedYes

Fingerprint

Connexin 43
Mosaicism
Atrial Fibrillation
Mutant Proteins
Cardiac Arrhythmias
Lymphocytes
Frameshift Mutation
Mutation
Connexins
Pulmonary Veins
Nonsense Codon
Gap Junctions
Protein Transport
Nucleotides
Amino Acids
DNA
Genes

Keywords

  • arrhythmia
  • connexins
  • electrophysiology
  • fibrillation
  • gap junctions
  • genetics

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Paradigm of genetic mosaicism and lone atrial fibrillation : Physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. / Thibodeau, Isabelle L.; Xu, Ji; Li, Qiuju; Liu, Gele; Lam, Khanh; Veinot, John P.; Birnie, David H.; Jones, Douglas L.; Krahn, Andrew D.; Lemery, Robert; Nicholson, Bruce J; Gollob, Michael H.

In: Circulation, Vol. 122, No. 3, 20.07.2010, p. 236-244.

Research output: Contribution to journalArticle

Thibodeau, IL, Xu, J, Li, Q, Liu, G, Lam, K, Veinot, JP, Birnie, DH, Jones, DL, Krahn, AD, Lemery, R, Nicholson, BJ & Gollob, MH 2010, 'Paradigm of genetic mosaicism and lone atrial fibrillation: Physiological characterization of a connexin 43-deletion mutant identified from atrial tissue', Circulation, vol. 122, no. 3, pp. 236-244. https://doi.org/10.1161/CIRCULATIONAHA.110.961227
Thibodeau, Isabelle L. ; Xu, Ji ; Li, Qiuju ; Liu, Gele ; Lam, Khanh ; Veinot, John P. ; Birnie, David H. ; Jones, Douglas L. ; Krahn, Andrew D. ; Lemery, Robert ; Nicholson, Bruce J ; Gollob, Michael H. / Paradigm of genetic mosaicism and lone atrial fibrillation : Physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. In: Circulation. 2010 ; Vol. 122, No. 3. pp. 236-244.
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abstract = "Background: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF. Methods and results: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins. Conclusions: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.",
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T2 - Physiological characterization of a connexin 43-deletion mutant identified from atrial tissue

AU - Thibodeau, Isabelle L.

AU - Xu, Ji

AU - Li, Qiuju

AU - Liu, Gele

AU - Lam, Khanh

AU - Veinot, John P.

AU - Birnie, David H.

AU - Jones, Douglas L.

AU - Krahn, Andrew D.

AU - Lemery, Robert

AU - Nicholson, Bruce J

AU - Gollob, Michael H.

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N2 - Background: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF. Methods and results: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins. Conclusions: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.

AB - Background: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF. Methods and results: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins. Conclusions: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.

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