The Unfolding Tail of CHIP Mutation in Gordon Holmes Syndrome

Gordon Holmes Syndrome (GHS) is a rare neurodegenerative disorder characterized by cerebellar ataxia with hypogonadism. The pathophysiological mechanisms and genetic causes of GHS are largely unknown and therapies limited. We identified a homozygous mutation (c.737C→T, p.Thr246Met) in STIP1 homology and U‐box containing protein 1 (STUB1), the gene that encodes for C‐terminus of Hsp70 Interacting Protein (CHIP) in siblings that presented with GHS. CHIP plays a central role in regulating protein quality control as both an E3 ligase and molecular chaperone. Human mutations of CHIP are increasingly linked to ataxias, but the molecular mechanisms underlying this disease pathology remain undefined. Biophysical and cell culture studies reveal T246M CHIP has a disorganized Ubox domain and exists mostly as aggregates. Consequently, T246M CHIP exhibits loss of E3 ligase activity, but unexpectedly, the amount of T246M CHIP interacting with substrates, E2 enzymes and molecular chaperones is higher than wild‐type CHIP. We hypothesize that the sequestering of CHIP interacting proteins drives disease pathology. Interestingly, T246M CHIP maintains some chaperone activity as measured by its in vitro potentiation of AMPK and translocation/activation of HSF1 in cells. Thus the T246M mutation disrupts CHIP structure and function resulting in a dominant negative protein impairing ubiquitin‐dependent protein degradation. We developed a T246M CHIP mouse model of GHS and present preliminary data consistent with our hypothesis that T246M CHIP functions as a dominant negative protein causing GHS.