PDYN – Spinocerebellar Ataxia Type 23

Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and dysarthria. Pathogenic missense and frameshift variants in PDYN, the gene encoding the opioid neuropeptide precursor prodynorphin, have been identified in multiple unrelated families with co-segregation of disease. Initial linkage and sequencing in four Dutch families revealed three missense mutations clustering in the dynorphin A (DynA) domain and one in the nonopioid region, with segregation across affected relatives (4 families) (PMID:21035104). Subsequent screening in two Japanese families (5 affected individuals) identified the recurrent c.644G>A (p.Arg215His) variant with intrafamilial phenotypic variability, including overlap with multiple system atrophy features (PMID:32587707). Further mutation analysis in 371 European ataxia cases uncovered three novel DynA-domain missense variants and one two-base‐pair deletion, absent in controls (PMID:23471613).

In total, at least 13 probands across six families harbor PDYN variants—predominantly missense changes in DynA (e.g., c.644G>A (p.Arg215His)) and a frameshift c.658_659del (p.Trp220fs). These variants consistently exhibit autosomal dominant inheritance with affected relatives in multiple pedigrees and hotspot clustering within the DynA coding region.

Functional assays demonstrate that several DynA mutants increase peptide production, induce greater cytotoxicity in cultured striatal neurons, and alter KOR signaling with reduced G-protein activation and β-arrestin recruitment compared to wild-type DynA (PMID:21035104; PMID:34944698). A knock-in mouse model carrying the recurrent p.Arg212Trp variant recapitulates key features of SCA23, including elevated mutant DynA levels, Purkinje cell loss, glutamate receptor dysregulation, and progressive motor deficits (PMID:26169942).

Collectively, the genetic and experimental data support a toxic gain-of-function mechanism whereby dynorphin A mutants accumulate and drive glutamate-mediated excitotoxicity leading to Purkinje neuron degeneration. No conflicting studies have been reported to dispute this association.

Clinical Validity and Utility

• The PDYN–SCA23 association is classified as Strong based on segregation in six families, 13 probands, and concordant functional and animal model evidence.
• Key take-home: Genetic testing for PDYN missense variants in patients with dominantly inherited cerebellar ataxia and dysarthria can provide molecular diagnosis, inform prognosis, and guide future therapeutic strategies targeting mutant dynorphin A toxicity.

References

• American journal of human genetics • 2010 • Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. PMID:21035104
• Cerebellum & ataxias • 2020 • Intrafamilial phenotypic variation in spinocerebellar ataxia type 23. PMID:32587707
• Journal of neurology • 2013 • Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases. PMID:23471613
• Brain : a journal of neurology • 2015 • Elevated mutant dynorphin A causes Purkinje cell loss and motor dysfunction in spinocerebellar ataxia type 23. PMID:26169942
• Biomedicines • 2021 • Functional Characterization of Spinocerebellar Ataxia Associated Dynorphin A Mutant Peptides. PMID:34944698

PDYN • spinocerebellar ataxia type 23

Evidence Based Scoring (AI generated)