Abstract
Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.
Highlights
Inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders characterized by adult-onset progressive cerebellar ataxia
We suggest that a close follow up of STUB1 carriers in SCAR16 families is warranted
Our findings demonstrate similar functional and biochemical properties for the heterozygous STUB1 variants identified in this study and those of previously reported recessive variants associated with SCAR16
Summary
Inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders characterized by adult-onset progressive cerebellar ataxia. The first reported Spanish family had a cognitive-affective syndrome (CCAS) and late-onset SCA following an autosomal dominant inheritance pattern [4]. 18 heterozygous pathogenic STUB1 variants have been reported to be associated with a SCA48 phenotype; how these mutations affect protein structure and the function remains unclear. Bi-allelic mutations in STUB1 cause autosomal recessive spinocerebellar ataxia (SCAR16), an early-onset disorder with gait disturbance, dysarthria, head and hand tremor, hyperreflexia, cognitive decline, and, occasionally, hypogonadism [12]. SCAR16 variants are thought to destabilize the CHIP structure and lead to mutation-specific abnormalities such as decreased interaction with chaperones, reduced steady-state cellular levels, reduced ubiquitination activity, and/or misfolding [13,14]. Our results suggest that the variants causing SCA48 are indistinguishable with regard to their functional impairment from previously described variants reported in families with SCAR16
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