Elucidation of pathological mechanism caused by human disease mutation in CaMKIIβ.

Recently, we have identified CaMKIIα and CaMKIIβ mutations in patients with neurodevelopmental disorders by whole exome sequencing study. Most CaMKII mutants have increased phosphorylation of Thr286/287, which induces autonomous activity of CaMKII, using cell culture experiments. In this study, we explored the pathological mechanism of motor dysfunction observed exclusively in a patient with Pro213Leu mutation in CaMKIIβ using a mouse model of the human disease. The homozygous CaMKIIβ Pro213Leu knockin mice showed age-dependent motor dysfunction and growth failure from 2 weeks after birth. In the cerebellum, the mutation did not alter the mRNA transcript level, but the CaMKIIβ protein level was dramatically decreased. Furthermore, in contrast to previous result from cell culture, Thr287 phosphorylation of CaMKIIβ was also reduced. CaMKIIβ Pro213Leu knockin mice showed similar motor dysfunction as CaMKIIβ knockout mice, newly providing evidence for a loss of function rather than a gain of function. Our disease model mouse showed similar phenotypes of the patient, except for epileptic seizures. We clearly demonstrated that the pathological mechanism is a reduction of mutant CaMKIIβ in the brain, and the physiological aspects of mutation were greatly different between in vivo and cell culture.