Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP

Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exomemutations in the E3 ligase RNF216 and deubiquitinase OTUD4.We performed exome sequencing in a family withtwoof three siblings afflictedwith ataxiaandhypogonadismandidentifiedahomozygousmutation in STUB1(NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus ofHSC70-interacting protein).CHIPplays acentral role in regulating protein quality control, in part throughits ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several geneticmousemodels of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimichumanataxiaand hypogonadism.We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.