Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments...

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• STUB1 gene variants are linked to spinocerebellar ataxias, including autosomal recessive SCAR16 and dominant SCA48.
• SCA48 presents with later-onset ataxia, cognitive issues, and overlaps with SCAR16, but its molecular basis is poorly understood.

Purpose of the Study:

• To investigate the molecular properties of dominant STUB1 variants associated with SCA48.
• To compare the biochemical defects of dominant and recessive STUB1 variants.

Main Methods:

• Analysis of three novel dominant STUB1 variants in SCA48 families.
• In vitro biochemical assays including ubiquitin ligase activity, circular dichroism, and native polyacrylamide gel electrophoresis on recombinant CHIP variants.

Main Results:

• Identified three novel dominant STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, p.Gly249Val) in SCA48 patients with late-onset ataxia and cognitive phenotypes.
• Demonstrated that both dominant and recessive STUB1 variants exhibit similar biochemical defects, including reduced ubiquitin ligase activity and altered CHIP oligomerization.

Conclusions:

• Dominant STUB1 variants cause molecular defects comparable to recessive variants, expanding the understanding of SCA48.
• Findings necessitate re-evaluation of assumptions regarding unaffected carriers of recessive STUB1 variants in SCAR16 families.
• Further research is required to clarify the disease status of SCAR16 heterozygotes and the molecular link between SCA48 and SCAR16.