PPP2R2B – Spinocerebellar Ataxia Type 12

Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the 5′ untranslated region of PPP2R2B, encoding the brain-specific regulatory subunit Bβ of protein phosphatase 2A (Gene Symbol; Disease Name). Affected individuals typically present in mid‐adulthood with action tremor, gait disturbance, dysmetria, and hyperreflexia.

Genetic evidence for PPP2R2B–SCA12 includes identification of expanded CAG repeats (>43 repeats) segregating in at least eight unrelated families (5 Indian families, 2 Italian kindreds, 1 Chinese family) encompassing over 30 affected individuals, with autosomal dominant inheritance and complete cosegregation in multipoint pedigrees ([PMID:11761478], [PMID:20629122], [PMID:25586539]). The CAG expansion has been observed in diverse ethnic backgrounds, supporting a recurrent or founder effect in certain populations. No other pathogenic variants have been implicated in SCA12.

Phenotypic spectrum extends beyond cerebellar atrophy to include cerebral white matter changes on MRI, prominent in one Chinese kindred presenting with action tremor and hyperreflexia ([PMID:25586539]). Phenotypic heterogeneity underscores the necessity of genetic testing in individuals with atypical tremor presentations that may mimic essential tremor ([PMID:38854909]).

Functional studies demonstrate that expanded repeats may alter PPP2R2B expression via promoter, splicing, or transcript stability changes. Neuropathological examination of an SCA12 brain confirmed both cerebellar and cortical atrophy with Purkinje cell loss and absence of polyglutamine aggregates, consistent with a toxic RNA or dysregulated phosphatase mechanism ([PMID:27748686]).

Cellular models, including an induced pluripotent stem cell line derived from an SCA12 patient, retain pluripotency and can be differentiated to neuronal subtypes to study pathogenic mechanisms and test therapeutic strategies ([PMID:38340452]). Two nonmutually exclusive hypotheses have been proposed: altered PPP2R2B expression impacting PP2A activity and direct toxicity of repeat‐containing transcripts.

Collectively, genetic and experimental data establish PPP2R2B CAG expansions as a definitive cause of autosomal dominant SCA12, with strong segregation and concordant functional evidence. Genetic testing for CAG repeat length in PPP2R2B should be part of the diagnostic workup for adult‐onset tremor and ataxia, enabling accurate diagnosis, family counseling, and targeted research.

Key Take-home: PPP2R2B CAG repeat expansions cause autosomal dominant SCA12, characterized by tremor and ataxia, with definitive genetic and mechanistic support for clinical testing.

References

• Annals of neurology • 2001 • Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. PMID:11761478
• Movement disorders : official journal of the Movement Disorder Society • 2010 • Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia. PMID:20629122
• Journal of the neurological sciences • 2015 • Unusual cerebral white matter change in a Chinese family with Spinocerebellar ataxia type 12. PMID:25586539
• Current opinion in neurology • 2016 • Spinocerebellar ataxia type 12: clues to pathogenesis. PMID:27748686
• Stem cell research • 2024 • Generation of an Induced pluripotent stem cell (iPSC) line (IGIBi011-A) from a Spinocerebellar ataxia type 12 gait dominant patient. PMID:38340452
• Tremor and other hyperkinetic movements (New York, N.Y.) • 2024 • Careful Phenotypic Characterization of Tremor Phenomenology in a Patient with Spinocerebellar Ataxia Type 12-Tremor Features Do Not Match Those of Essential Tremor. PMID:38854909
• Human molecular genetics • 2025 • De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias. PMID:39565297

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