The cooccurrence of intermediate (40-49 CAG/CAA) TBP repeat expansions with STUB1 variants questions the pathogenicity of monoallelic STUB1 variants in cerebellar ataxia. The objective of this study was to describe the phenotypic spectrum of heterozygous STUB1 variants with or without intermediate TBP repeat expansions. We determined the presence of TBP repeat expansions and STUB1 variants in six families with cerebellar ataxia. Cooccurrence of both genotypes in one family resulted in cerebellar ataxia, involving cognitive and extrapyramidal complications. Variable degrees of cerebellar ataxia and cognitive impairment were found in four families carrying a heterozygous STUB1 variant and normal TBP alleles. Finally, we report one patient with a mild late-onset cerebellar ataxia carrying an intermediate expanded TBP allele without the presence of a STUB1 variant. Heterozygous STUB1 variants are associated with a milder phenotype and reduced penetrance compared with the cosegregation with intermediate TBP alleles, which causes a fully penetrant complicated form of cerebellar ataxia. © 2025 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxias (SCAs) encompass a wide spectrum of inherited neurodegenerative diseases, primarily characterized by pathological changes in the cerebellum, spinal cord, and brainstem degeneration. Autosomal dominant spinocerebellar ataxia type 48 (SCA48) is a newly identified subtype of SCA, marked by early-onset ataxia and cognitive impairment, and is associated with mutations in the STIP1 homology and U-box-containing protein 1 (STUB1) gene. The STUB1 gene encodes the protein CHIP (C-terminus of HSC70-interacting protein) which functions as E3 ubiquitin ligase and is crucial to the development of neural systems. Here, we reported a Chinese SCA48 family exhibited typical features and defined a novel missense mutation STUB1 c.755A>C (CHIP p. Y252S) through whole-exome sequencing. The variant was interpreted as a variant of uncertain significance, so we conducted a series of experiments using minigene plasmids to evaluate the pathogenicity of the variant. We found that the variant STUB1 c.755A>C caused a significant reduction of CHIP level and the loss function of ubiquitin ligase activity as the pathogenic STUB1 mutations reported before. Besides, we also found that the CHIP p. Y252S could cause tau aggregation, which is considered to contribute to the progression of neurodegenerative disorders. We diagnose the SCA48 pedigree in China and highlight the role of decreased ubiquitination and increased tau aggregation in the pathogenesis of the novel STUB1 c.755C>A mutation.

Spinocerebellar ataxia type 48 (SCA48) is an autosomal dominantly inherited disease characterized by gait and limb ataxia, cerebellar dysarthria, cognitive impairment, psychiatric abnormalities and variable types of movement disorders. To date, more than 30 STUB1 gene (NM_005861.4) mutations have been described in the genetic background of The aim of this short report was to demonstrate the first Hungarian SCA48 patient caused by a novel STUB1 missense mutation. The characteristics of detailed neurological phenotype, brain MRI and genetic assessment are presented and compared to previously published case. The most important neurological findings of the patient were gait ataxia, dysarthria, cognitive decline and psychiatric problems including depression, anxiety and mild impulsivity. The brain MRI demonstrated cerebellar atrophy with posterolateral predominance and frontal lobe cortical atrophy. Clinical exome sequencing examination identified the above-mentioned missense variant located in the significant ubiquitinase domain of the CHIP protein. In this paper the first Hungarian SCA48 patient was described with characteristic neuropsychiatric signs and brain MRI abnormalities, due to a novel STUB1 gene missense mutation. A spinocerebellaris ataxia 48-as típusa (SCA48) autoszomális domináns módon öröklődő betegség, aminek legjellemzőbb tünetei a járási és végtagataxia, a cerebellaris dysarthria, a kognitív deficit, a pszichiátriai eltérések és a különböző mozgászavarok. Eddig több mint 30 génmutációt azonosítottak az SCA48 hátterében. Az esetismertetés célja, hogy bemutassa az első magyar SCA48-as családot, akiknél a kórképet egy új misszensz mutáció okozza. Az esetismertetés részletes leírást ad a neurológiai fenotípusról, a koponya-MR-eltérésekről és a genetikai háttérről, illetve összehasonlítja ezeket a korábban közölt esetekben megfi-gyelt jellemzőkkel. A beteg legfontosabb neurológiai tünetei a járási ataxia, a dysarthria és a kognitív hanyatlás voltak, melyek mellett pszichiátriai tünetek is jelentkeztek: depresszió, anxietas és enyhe impulzivitás. A koponya- MR-vizsgálat posterolateralis túlsúlyú kisagyi és frontális lebenyi kérgi atrophiát jelzett. A klinikai exomszekvenálás során a fent említett misszensz variáns igazolódott, ami a CHIP protein nagy jelentőségű ubiquitinase funkciójú doménjében található. Jelen esetismertetés bemutatja az első magyar, új génmutáció okozta SCA48-as beteg jellegzetes neuropszichiátriai tüneteit és koponya-MR-eltéréseit.