Further functional evidence that RNF170 deficiency may cause HSP via a loss-of-function mechanism is derived from functional studies that (i) demonstrated reduced expression of RNF170 transcript and absence of RNF170 protein in patient fibroblasts (family A, Fig. 1f), (ii) increased basal levels and deficient stimulus-dependent degradation of IP3R-3 in patient fibroblasts-expressing mutant RNF170 protein (family A and C) as well as (iii) increased basal levels of IP3R-1 in neuronal SH-SY5Y cells and rescue by re-expression of RNF170wt. Here, ITPR1 is linked to hereditary spastic paraplegia.