title: Modeling Andersen's Syndrome in Human Induced Pluripotent Stem Cells.
abstract: Andersen's syndrome (AS) is a rare disorder characterized by a triad of symptoms: periodic paralysis, cardiac arrhythmia, and bone developmental defects. Most of the patients carry mutations on the inward rectifier potassium channel Kir2.1 encoded by the KCNJ2 gene. kcnj2 knockout mice are lethal at birth preventing, hence, thorough investigations of the physiological and pathophysiological events. We have generated induced pluripotent stem (iPS) cells from healthy as well as from AS patient muscular biopsies using the four-gene cassette required for cellular reprogramming (Oct4, Sox2, Klf4, and c-Myc). The generated AS-iPS cells exhibited the gold standard requirement for iPS cells: expression of genetics and surface pluripotent markers, strong alkaline phosphatase activity, self-renewal, and could be differentiated by the formation of embryoid bodies (EBs) into the three germ layers. Sequencing of the entire coding sequence of the KCNJ2 gene, in AS-iPS cells, revealed that the reprogramming process did not revert the Andersen's syndrome-associated mutation. Moreover, no difference was observed between control and AS-iPS cells in terms of pluripotent markers' expression, self-renewal, and three germ layer differentiation. Interestingly, expression of osteogenic markers are lower in EB-differentiated AS-iPS compared to control iPS cells. Our results showed that the Kir2.1 channel is not important for the reprogramming process and the early step of the development in vitro. However, the osteogenic machinery appears to be hastened in AS-iPS cells, strongly indicating that the generated AS-iPS cells could be a good model to better understand the AS pathophysiology.
authors.affiliation: 1 UMR7370 CNRS, LP2M, Labex ICST, Faculté de Médecine, University Nice Sophia Antipolis , Nice, France .
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pini
authors.affiliation: 1 UMR7370 CNRS, LP2M, Labex ICST, Faculté de Médecine, University Nice Sophia Antipolis , Nice, France .
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rouleau
authors.affiliation: 2 INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN) , Nice, France .|3 CNRS, UMR 7284, Institute for Research on Cancer and Aging of Nice (IRCAN) , Nice, France .|4 Faculty of Medicine, Neuromuscular Diseases and ALS Specialized Center, University of Nice-Sophia-Antipolis , Nice, France .
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.affiliation: 2 INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN) , Nice, France .|3 CNRS, UMR 7284, Institute for Research on Cancer and Aging of Nice (IRCAN) , Nice, France .|4 Faculty of Medicine, Neuromuscular Diseases and ALS Specialized Center, University of Nice-Sophia-Antipolis , Nice, France .
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: 1 UMR7370 CNRS, LP2M, Labex ICST, Faculté de Médecine, University Nice Sophia Antipolis , Nice, France .
authors.forename: Saïd
authors.initials: S
authors.lastname: Bendahhou
mesh_terms: D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D058732:Embryoid Bodies / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005855:Germ Layers / Q000378:metabolism; D006011:Glycogen Storage Disease Type IV / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000090062:Kruppel-Like Factor 4