In ADSA on the other hand, reduced levels of RNF170 do not translate into increased IP3R signaling, as IP3R levels are unaltered in patient lymphoblasts and Ca2+ release from the ER is even decreased in this model contrary to expectations.9 We suggest a toxic gain of function mechanism for the ADSA missense variant that is unrelated to transcript dosage effects; this hypothesis is supported by the dose-dependent toxicity of RNF170Arg199Cys in zebrafish larvae26. This evidence concerns the gene ITPR3 and autosomal dominant sensory ataxia 1.