Paradigm of Genetic Mosaicism and Lone Atrial Fibrillation

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 dominantnegative 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. (Circulation. 2010;122:236-244.)

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

“…Cells expressing mutant connexins showed a significant loss of function in the ability to electrically couple paired cells. the identified 40 this latter finding provides strong support for the concept of heteromeric interaction of Cx40 and Cx43 in hemichannel formation.…”

“…40 the frameshift mutation (c.932delC) was identified in an otherwise healthy female who was diagnosed with af at 48 years of age following a longstanding history of palpitations. the single base pair deletion resulted in a truncated C-terminal domain of connexin 43 containing 36 aberrant amino acids.…”

A Connexin50 Mutant, CX50fs, That Causes Cataracts Is Unstable, but Is Rescued by a Proteasomal Inhibitor

“…1). Identification of connexin mutants has linked alterations of connexins and their functions to human diseases including demyelinating neuropathies, oculodentodigital dysplasia, skin disorders, deafness, arrhythmias, and cataracts (2)(3)(4)(5)(6)(7)(8)(9).…”

“…Many mutants have reduced or absent channel function or form channels/ hemichannels with altered gating or permeability (2,3,(5)(6)(7)(8)(9). Many mutants show alterations in their cellular behaviors including impaired trafficking or degradation that can lead to accumulation of the abnormal protein (2,3,(5)(6)(7)(8)(9). Several of the CX46 and CX50 mutants linked to cataracts have been thoroughly studied (10 -17).…”

A novel GATA5 loss-of-function mutation underlies lone atrial fibrillation

“…Genome-wide linkage analysis with polymorphic genetic markers mapped multiple susceptibility loci for AF on human chromosomes 10q22, 6q14-16, 11p15.5, 5p13, 10p11-q21 and 5p15, of which AF-causing mutations in 2 genes, KCNQ1 on chromosome 11p15.5 and NUP155 on chromosome 5p13, were identified and functionally characterized (15)(16)(17)(18)(19)(20)(21). Additionally, a genetic scan of candidate genes revealed a long list of AF associated genes, including KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, NPPA, GJA1 and GJA5 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Nevertheless, AF is a genetically heterogeneous disease and the genetic determinants for AF in a large proportion of patients remain unclear.…”