SPTBN2 – Spinocerebellar Ataxia Type 5

Spinocerebellar ataxia type 5 (SCA5) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar dysfunction, including unsteady gait, dysarthria, and ocular motor abnormalities. The disease is caused by heterozygous mutations in the SPTBN2 gene encoding β-III spectrin (SPTBN2), and annotated in Monarch as Spinocerebellar Ataxia Type 5.

Genetic studies have identified more than 19 distinct SPTBN2 variants in over 23 unrelated probands, demonstrating an autosomal dominant inheritance pattern with full penetrance in adulthood but with infantile-onset presentations described in several cases ([PMID:16429157], [PMID:22914369]). Reported pathogenic variants include in-frame deletions and missense substitutions within spectrin repeat or actin-binding domains, such as the heterozygous c.1438C>T (p.Arg480Trp) variant associated with infantile-onset global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia ([PMID:22914369]).

Segregation analysis in multiple pedigrees confirms cosegregation of SPTBN2 mutations with disease. For example, a Japanese SCA5 family with five affected members across two generations harbored the novel c.2608_2610del (p.Glu870del) variant, segregating in all affected relatives and absent in unaffected kin ([PMID:25142508]). In total, at least four additional affected relatives have been documented to carry pathogenic SPTBN2 alleles.

The variant spectrum encompasses missense changes (e.g., c.1309C>G (p.Arg437Gly), c.1052G>C (p.Arg351Pro)), small in-frame deletions (e.g., c.1596_1634del (p.Glu532_Met544del)), and frameshift/truncating alleles. Infantile-onset cases tend to harbor ABD-localized missense mutations with more severe phenotypes, including global developmental delay (HP:0001263), hypotonia (HP:0001252), clumsiness (HP:0002312), tremor (HP:0001337), and unsteady gait (HP:0002317) ([PMID:30898343], [PMID:31721007]).

Functional assays and animal models demonstrate that mutant β-III spectrin fails to stabilize the glutamate transporter EAAT4 at Purkinje cell membranes and results in altered actin-binding affinity. Mouse knockouts recapitulate Purkinje cell loss, cerebellar atrophy, gait abnormalities, reduced sodium currents, and glutamatergic dysregulation ([PMID:20371805]). Biophysical studies of nine ABD mutants showed destabilized CH1-CH2 interfaces and increased F-actin binding affinity, supporting a toxic gain-of-function mechanism ([PMID:37626910]).

Integration of genetic and experimental data supports a Strong ClinGen classification for the SPTBN2–SCA5 association. The breadth of pedigrees, consistent segregation, recurrent variant types, and concordant functional disruption of β-III spectrin underpin robust diagnostic and research utility. Key Take-home: Heterozygous SPTBN2 mutations cause dominantly inherited SCA5 via disrupted spectrin-mediated membrane stabilization, guiding genetic testing and potential therapeutic targeting.

References

• Nature Genetics • 2006 • Spectrin mutations cause spinocerebellar ataxia type 5 PMID:16429157
• Journal of Child Neurology • 2013 • Case of infantile onset spinocerebellar ataxia type 5. PMID:22914369
• Journal of Human Genetics • 2014 • A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study. PMID:25142508
• Brain & Development • 2019 • Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: A case report. PMID:30898343
• The Journal of Neuroscience • 2010 • Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. PMID:20371805
• Cells • 2023 • Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin PMID:37626910

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