PREDACTING : Predicting the clinical outcome of non-muscle actinopathies

Actins are abundantly produced proteins playing crucial roles in critical cellular processes. Mutations in ACTB and ACTG1 (beta- and gamma-cytoskeletal actin isoforms) cause a broad spectrum of rare disorders – Nonmuscle actinopathies (NMAs). NMAs show high clinical variability. The underlying mechanisms remain to be resolved. We assume that the clinical outcome of NMAs is associated with the specific site/type of mutation, thus affecting actin’s role as transcriptional co-factor and as major component of the cytoskeleton, binding substrate for multiple partners, and track for molecular motors. Our preliminary data show mutation specific cellular phenomena that can be used as a functional readout to predict the clinical outcome in a patient. We propose to systemize clinical information, providing reliable genotype-phenotype correlation, explore cellular disease mechanisms on a multiple- scale level spanning from single molecules to model organism, and develop praxis-oriented screening methods for the functional interpretation of rare actin variants. We bring together five research groups with outstanding expertise, which includes actomyosin physiology, molecular genetics and structure, cell force spectroscopy, high-resolution light and atomic force microscopy, in vivo imaging, C. elegans model system, as well as unique knowledge of the NMA clinical spectrum. Our results will allow a substantial revision of current management strategies, lay out the basis for future clinical studies and provide broadly applicable functional assays allowing for genotype-phenotype correlation.