Changes in protein function underlies the disease spectrum in patients with CHIP mutations

Abstract

Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 (SCAR16) is caused by coding mutations in STUB1, a gene that encodes the multi-functional enzyme CHIP (C-terminus of HSC70-interacting protein). The spectrum of disease found in SCAR16 patients includes a wide range in the age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism. Although SCAR16 mutations span the multiple functional domains of CHIP, it is unclear if the location of the mutation contributes to the clinical spectrum of SCAR16 or with changes in the biochemical properties of CHIP. In this study, we examined the associations and relationships between the clinical phenotypes of SCAR16 patients and how they relate to changes in the biophysical, biochemical, and functional properties of the corresponding mutated protein. We found that the severity of ataxia did not correlate with age of onset; however, cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity. We further identified domain-specific relationships between biochemical changes in CHIP and clinical phenotypes, and specific biochemical activities that associate selectively to either increased tendon reflex or cognitive dysfunction, suggesting that specific changes to CHIP-HSC70 dynamics contributes to the clinical spectrum of SCAR16. Finally, linear models of SCAR16 as a function of the biochemical properties of CHIP support the concept that further inhibiting mutant CHIP activity lessens disease severity and may be useful in the design of patient-specific targeted approaches to treat SCAR16. ataxia | aging | ubiquitin | protein quality control | modeling disease 1 These authors contributed equally to this work 2