Yiqing Yang

Identification of a KCNE2 Gain-of-Function Mutation in Patients with Familial Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation.

Accumulating evidence reveals that genetic variants play pivotal roles in familial atrial fibrillation (AF). However, the molecular defects in most patients with AF remain to be identified. Here, we report on three novel KCNA5 mutations that were identified in 4 of 120 unrelated AF families. Among them, T527M was found in two AF families, and A576V and E610K in two other AF families, respectively. The mutations T527M and A576V were also detected in 2 and 1 of 256 patients with idiopathic AF, respectively. The same mutations were not observed in 200 secondary AF patients and 500 controls. Functional analyses revealed consistent loss-of-function effects of mutant KCNA5 proteins on the ultrarapidly activating delayed rectifier potassium currents. These findings expand the spectrum of mutations in KCNA5 linked to AF and provide new insight into the molecular mechanism involved in AF.

Unique Histological Features of the Left Atrial Posterior Wall

The left atrial posterior wall (LAPW) plays a critical role in atrial fibrillation, but the underlying mechanism remains unclear. In the present study, we sought to characterize the histological features of the LAPW. Different atrial regions were dissected from hearts of normal Sprague-Dawley rats and humans. Haematoxylin/eosin and van Gieson staining were used to analyse atrial cardiomyocyte arrangement and collagen distribution, respectively. Intercellular junctions were evaluated by transmission electron microscopy. In contrast with other atrial regions, the LAPW exhibited more disorganized cardiomyocytes, larger intercellular spaces and variable myocardial fibre arrangement. The proportion of collagen was significantly higher in the LAPW than in other atrial regions. Interestingly, desmosomes were sparse along with intercellular gaps in the LAPW. In summary, distinct disarrangement of cardiomyocytes and an abundance of collagen exist in the LAPW. The sparsity of desmosomes in the LAPW may be related to the heterogeneous distribution and separation of atrial myocytes.