Andersen’s syndrome (AS) is complex disorder with patient phenotypes mixing periodic paralyses, cardiac arrhythmia, bone malformation, and cognitive abnormalities. We have made progress understanding how mutations in the KCNJ2, the only gene associated with AS, can lead to electrical dysfunctions in both skeletal and cardiac muscles. The involvement of Kir2.1 channels in AS has emphasized the physiological importance of sarcolemmal inward rectifiers in regulating cellular excitability. However, our understanding of the fundamental molecular and biophysical mechanisms responsible for Kir2.1 dysfunction and an explanation for dominant negative mutant channel behavior in this disorder are incomplete. Moreover, the contribution of Kir2.1 to muscle excitability and bone development remains to be elucidated. The actual project will focus on determining the role of the Kir2.1 channel in excitability and bone morphogenesis in vitro and in vivo, using biopsies from AS patients and animal models. We have used AS muscle biopsies to understand the role of the potassium channels in both skeletal muscle excitability and bone morphogenesis. If muscle biopsies may be appropriate in addressing skeletal muscle issues, this may have some limitations in other tissues. Reprogramming of human somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into the 3 germ layers is a new powerful technology that offers an attractive tool to model human developmental pathways1. Furthermore, disease-specific iPSCs allow an unprecedented experimental plateform for basic research as well as high throughput screening2. This may be particularly relevant for developmental disorders in which the effects on cells during the early life are not accessible. We will take advantage of the availability of three AS muscle biopsies (along with biopsies from controls) to generate human AS-specific iPSCs. A combination of transcriptomics and proteomic analyses, immunohistochemistry, microscopy imaging, and 2-photon Ca2+ imaging will be used to determine the role of the Kir2.1 potassium channel in cell excitability as well as during the different key steps of bone morphogenesis.
1 Takahashi K, et al. (2007) Cell 131: 861-72.
2 Park IH, et al. (2008) Cell 134: 877‐86.
CNRS-UMR 7370 -Laboratoire de Physiomedecine moléculaire, Université de Nice-Sophia antipolis Faculté de Médecine, 28 Av Valombrose, Tour Pasteur
06108 Nice, France. e-mail to Said Bendahhou