Human iPS cell models of Jervell and Lange-Nielsen syndrome.
Recessive mutations in the ion channel-encoding KCNQ1 gene may cause Jervell and Lange-Nielsen syndrome (JLNS), a fatal cardiac disease leading to arrhythmia and sudden cardiac death in young patients. Mutations in KCNQ1 may also cause a milder and dominantly inherited form of the disease, long QT syndrome 1 (LQT1). However, why some mutations cause LQT1 and others cause JLNS can often not be understood a priori. In a recent study,(1) we have generated human induced pluripotent stem cell (hiPSC) models of JLNS. Our work mechanistically revealed how distinct classes of JLNS-causing genetic lesions, namely, missense and splice-site mutations, may promote the typical severe features of the disease at the cellular level. Interestingly, the JLNS models also displayed highly sensitive responses to pro-arrhythmic stresses. We hence propose JLNS hiPSCs as a powerful system for evaluating both phenotype-correcting as well as cardiotoxicity-causing drug effects.
Department of Anatomy and Embryology; Leiden University Medical Center ; Leiden, The Netherlands.
Milena
M
Bellin
Human Stem Cell Pluripotency Group; Max Planck Institute for Molecular Biomedicine ; Münster, Germany ; Chemical Genomics Center of the Max Planck Society ; Dortmund, Germany.
Boris
B
Greber
cardiac differentiation; disease modeling; drug testing; human iPS cells; Jervell and Lange-Nielsen syndrome