Mutations in Connexin43 and Connexin40 Associated with Human Atrial Fibrillation; Physiology and Mechanism

Atrial Fibrillation (AF), the most common sustained cardiac arrhythmia, is a disease that affects the electrical conductance in the atria. Gap junction channels, composed of connexin (Cx) proteins, allow the electrical signal to propagate between cardiac myocytes. Mutations in two highly expressed cardiac connexin genes, GJA1 (Cx43) and GJA5 (Cx40), have been identified by our group in a cohort of patients with lone AF. To characterize trafficking of a novel somatic frameshift Cx43 mutant and three novel Cx40 mutants, fluorescently tagged connexins were visualized in HeLa cells using confocal microscopy. Electrophysiological studies were performed by a member of our lab to test the function of mutant gap junction channels. The Cx43 frameshift mutant (Cx43-932delC) caused intracellular retention of Cx43, resulting in impaired electrical coupling between paired cells. All three Cx40 mutants (F30L, G311S and R113S) demonstrated normal trafficking and electrical coupling between paired N2A cells. Enhanced hemichannel function was observed for the Cx40-F30L mutant, leading to cell death in Xenopus oocytes. Increased sensitivity to intracellular pH caused closure of gap junction channels composed of Cx40-G311S or Cx40-R113S. Intracellular localization of a previously published Cx40 mutation (P88S) was determined to be retained within the ER and Golgi compartments. Trafficking rescue was observed when P88S was co-expressed with wild-type Cx40 or Cx43. My results and those of our collaborators demonstrate a novel finding that a Cx43 mutation is associated with AF and also further support reported findings on the association of Cx40 mutations with AF.

Grantor dc:publisher

University of Ottawa (Canada)

Year dc:date

2013

Author dc:creator

• Thibodeau, Isabelle

• Biology, Molecular.

Language dc:language

en

Identifier

Source: Masters Abstracts International, Volume: 49-06, page: 3715.
http://dx.doi.org/10.20381/ruor-19463

OAI identifier oai:identifier

oai:ruor.uottawa.ca:10393/28834