Abstract 1881: Familial Isolated Cardiac Conduction Defect Associated with a Germ-Line Mutation in the Connexin40 Gene GJA5
Background: Gap junction (GJ) plays pivotal roles in the electrical coupling between two apposed cardiomyocytes thereby enabling normal impulse propagation. Isolated cardiac conduction defect (ICCD) is a hereditary lethal arrhythmia, characterized by slow conduction in the specialized conduction system without underlying structural heart diseases. GJ is therefore a candidate responsible for ICCD, although mutations have been identified only in the cardiac Na channel SCN5A so far.
Methods: We have screened GJ genes in three ICCD families, and identified a mutation in the connexin40 (Cx40) gene GJA5, a GJ predominantly expressed in atrium and the specialized conduction system. The proband was an asymptomatic 6 year-old boy with idioventricular rhythm, 1st degree AV block, and complete left bundle branch block. He developed multiple episodes of syncope afterwards and died suddenly at the age of 11 just before pacemaker implantation. His mother, also a sudden death victim after delivery, and his asymptomatic sister showed an ECG pattern nearly identical to the proband and no organic heart diseases.
Results: A missense mutation Q58L of GJA5 was found in the leukocyte genome of both proband and his sister, indicating a germ-line mutation. No mutations were found in SCN5A or other Cx genes. GJ-deficient neuroblastoma N2A cells transfected with a green fluorescent protein-tagged Cx40 showed clear GJ plaque at the cell-cell interface of wild-type (WT) cell pairs, whereas Q58L Cx40 was predominantly expressed in the intracellular space and the GJ formation was impaired. Intracellularly applied divalent dye Lucifer yellow readily transferred to the neighboring cells in WT, but was substantially delayed in the Q58L. Furthermore, junctional conductance measured by the dual whole-cell patch clamp were severely impaired in Q58L cell pairs (WT = 12.9 ± 5.8 nS, n = 4; Q58L = 1.2 ± 0.7 nS; n = 5; mean ± SD, p < 0.01), suggesting that the genetic defect of GJA5 disrupts cell-to-cell communication in the specialized conduction system, leading to manifest ICCD.
Conclusions: This is the first report of germ-line mutation in GJA5 responsible for ICCD, although somatic mutations of GJA5 in the cardiac tissues have been previously reported in patients with atrial fibrillation.