STUB1 – Spinocerebellar Ataxia 48

Spinocerebellar ataxia 48 (SCA48) is an adult-onset autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia in combination with a cerebellar cognitive-affective syndrome and variable extrapyramidal features. Clinical presentation typically includes gait disturbance, dysarthria, cognitive impairment, behavioral changes, dystonia, apraxia, and parkinsonism. SCA48 has been reported in multiple pedigrees of diverse ancestry (Dutch, Italian, Turkish, French, Australian), confirming its global relevance.

Pathogenic heterozygous variants in STUB1 (STIP1 homology and U-box containing protein 1), encoding the E3 ubiquitin ligase CHIP, underlie SCA48. At least 12 distinct truncating or missense variants disrupting the TPR or U-box domains have been described in >20 unrelated probands; the recurrent frameshift c.731_732del (p.Cys244TyrfsTer24) segregates with disease in a large Dutch family ([PMID:32337344]). Segregation analysis across multiple multi-generation pedigrees demonstrated autosomal dominant transmission with 23 affected relatives.

Reported variant classes include heterozygous frameshift mutations (e.g., c.731_732del (p.Cys244TyrfsTer24)), nonsense changes (e.g., c.829C>T (p.Gln277Ter)), and domain-spanning missense substitutions (e.g., p.Gly249Val). These alleles abolish CHIP ubiquitin ligase function, and monogenic cases uniformly lack pathogenic TBP repeat expansions, supporting a primary STUB1-driven mechanism.

Neuropathologic evaluation reveals ubiquitin/p62- and tau-positive neuronal inclusions in cerebellum, neocortex, and brainstem, indicative of impaired protein quality control. Cellular and animal models demonstrate that dominant STUB1 variants impair CHIP’s ubiquitin ligase activity, mislocalize CHIP in Purkinje cell dendrites, and disrupt chaperone interactions, recapitulating the human phenotype.

Initial hypotheses of digenic TBP/STUB1 inheritance have been refuted by monogenic case series in patients without TBP expansions ([PMID:38625442], [PMID:39680235]), confirming that STUB1 haploinsufficiency or dominant-negative effects are sufficient to cause SCA48.

Under ClinGen criteria, the STUB1–SCA48 association is classified as Strong: multiple unrelated pedigrees encompassing >20 probands, robust autosomal dominant segregation (23 affected relatives), and concordant neuropathologic and functional data. STUB1 should be included on adult ataxia gene panels to guide diagnosis, counseling, and future therapeutic development.

References

• Neurology Genetics • 2020 • Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation. [PMID:32337344]
• Neurogenetics • 2020 • Cerebellar cognitive-affective syndrome preceding ataxia associated with complex extrapyramidal features in a Turkish SCA48 family. [PMID:31741143]
• Parkinsonism & related disorders • 2019 • Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: A report of two Italian families. [PMID:31126790]
• Journal of neurology • 2021 • Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia. [PMID:33417001]
• Neurogenetics • 2024 • Two more families supporting the existence of monogenic spinocerebellar ataxia 48. [PMID:38625442]
• Cerebellum (London, England) • 2024 • Case Series of Cerebellar Ataxia with Tremor Due to Heterozygous STUB1 Variants (SCA48) without TBP Expansions: Further Evidence for SCA48 as a Monogenic Disease. [PMID:39680235]

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