Myocytes of patients with type 1 long-QT syndrome
exhibit prolongation of the action potential, altered IKs activation
and deactivation properties, and an abnormal response to catecholamine
stimulation with a protective effect of beta-blockade, study data have shown.
“Even though the incidence of the long-QT syndrome
is only one case per 2,500 live births, [type 1 long-QT syndrome] provides a
platform for showing the suitability of induced pluripotent stem-cell
technology as a means of exploring disease mechanisms in human genetic cardiac
disorders,” researchers wrote.
In the study, researchers screened a family affected by
type 1
long-QT syndrome, which included an 8-year-old boy and his
42-year-old father, 39-year-old aunt and 70-year-old grandfather. They
identified an autosomal dominant missense mutation (R190Q) in the KCNQ1
gene and collected dermal fibroblasts from two family members and two healthy
controls. The fibroblasts were then infected with retroviral vectors encoding
the human transcription factors OCT3/4, SOX2, KLF4
and c-MYC to generate pluripotent stem cells.
According to researchers, induced pluripotent stem cells
maintained the disease genotype of long-QT syndrome type 1 and generated
functional
myocytes. Expression of cell type-specific markers and
recordings of the action potentials in single cells indicated a
“ventricular,” “atrial” or “nodal” phenotype of
individual cells.
Additional characterization of the role of the
R190Q-KCNQ1 mutation in the syndrome’s pathogenesis suggested a dominant
negative trafficking defect, which was associated with a 70% to 80% reduction
in IKs current and altered channel activation and deactivation
properties. Furthermore, myocytes derived from patients with long-QT syndrome
type 1 had a heightened susceptibility to catecholamine-induced
tachyarrhythmia, which was attenuated by beta-blockade.
“Larger sets of long-QT syndrome cell lines
harboring different channel mutations will be needed to further validate the
disease phenotype and compare pathogenetic mechanisms in diverse forms of the
disease,” the researchers concluded. “Clinically, the severity of
manifestations of the long-QT syndrome varies among family members, and
incomplete penetrance exists. However, we did not observe any phenotypic
differences in the prolongation of the action potential between the myocytes
from our two patients, a finding that is probably due to the similarity of the
clinical phenotype in these cases.”