NOP56 – Spinocerebellar Ataxia Type 36

Spinocerebellar ataxia type 36 (SCA36), also known as Asidan, is an autosomal-dominant neurodegenerative disorder caused by a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56. This intronic expansion, annotated as c.3GGCCTG[16_?], segregates with disease in multiple families and leads to toxic RNA foci formation and neuronal inclusion bodies (PMID:24985895). Patients present with progressive cerebellar ataxia, cognitive impairment, and affective symptoms.

A genome-wide linkage analysis in three unrelated Japanese families (LOD 4.60) mapped the SCA36 locus to 20p13 and identified the intronic expansion in NOP56. Initial screening found expansions in 9 of 251 SCA cases and none in Alzheimer’s disease, ALS, or 300 controls (PMID:21683323). Subsequent fragment analysis in 577 undiagnosed ataxia patients identified 4 additional index cases (PMID:28761930), and a Japanese pedigree comprising 4 relatives including 2 affected individuals further confirmed the variant (PMID:38811808). In total, at least 15 unrelated probands have been documented with this expansion.

Clinical features include adult-onset gait ataxia (onset 35–50 years), dysarthria, ataxic or spastic limbs, abnormal ocular movements, cognitive impairment (HP:0100543), and depression (HP:0000716) (PMID:28761930; PMID:32270466). Cognitive-affective assessment in 30 carriers from the Costa da Morte cohort revealed 19 ataxic mutation carriers with impaired phonological and semantic fluency, and depression even in preataxic subjects, confirming high penetrance (PMID:32270466).

Functional studies demonstrated abundant (GGCCUG)n RNA foci in neuronal nuclei of the cerebrum, cerebellum, inferior olive, and spinal cord, often co-localizing with ubiquitin- and p62-positive inclusions in patient tissues (PMID:24985895). In lymphoblastoid cells from affected subjects, gel-shift assays showed specific binding of (GGCCUG)n to the splicing factor SRSF2, and neighboring MIR1292 transcription was reduced. RNA sequencing of patient blood revealed downregulation of ribosomal biogenesis and translation genes, supporting an RNA gain-of-function mechanism disrupting protein synthesis (PMID:38811808).

No studies to date dispute this association. The autosomal-dominant inheritance, ≥15 unrelated probands with complete segregation, and concordant functional evidence support a Strong clinical validity classification for NOP56 in SCA36.

Key Take-home: NOP56 GGCCTG repeat expansions are a validated cause of SCA36 with robust genetic and functional evidence to inform diagnostic testing and guide clinical management.

References

• European journal of neurology • 2014 • Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan). PMID:24985895
• Journal of human genetics • 2024 • Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation. PMID:38811808
• Neurology. Genetics • 2017 • Prevalence of spinocerebellar ataxia 36 in a US population. PMID:28761930
• Cerebellum (London, England) • 2020 • Cerebellar Cognitive Affective Syndrome in Costa da Morte Ataxia (SCA36). PMID:32270466
• American journal of human genetics • 2011 • Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. PMID:21683323

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