A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns
Spinocerebellar ataxia type 15 (SCA15) is a group of human neurodegenerative disorders characterized by a slowly progressing pure cerebellar ataxia. The inositol 1,4,5-trisphosphate (IP(3)) receptor type 1 (IP(3)R1) is an intracellular IP(3)-induced Ca(2+) release channel that was recently identified as a causative gene for SCA15. In most case studies, a heterozygous deletion of the IP(3)R1 gene was identified. However, one Japanese SCA15 family was found to have a Pro to Leu (P1059L) substitution in IP(3)R1. To investigate the effect of the P1059L mutation, we analyzed the channel properties of the mutant human IP(3)R1 by expressing it in an IP(3)R-deficient B lymphocyte cell line. The P1059L mutant was a functional Ca(2+) release channel with a twofold higher IP(3) binding affinity compared to wild-type IP(3)R1. The cooperative dependence of the Ca(2+) release activity of the mutant on IP(3) concentration was reduced, but both wild-type and mutant receptors produced similar B cell receptor-induced Ca(2+) signals. These results demonstrate that the Ca(2+) release properties of IP(3)R1 are largely unaffected by the P1059L mutation.