PTPA – Parkinson Disease

Recent studies have proposed an association between PTPA and Parkinson disease. Evidence stems from both case reports and a multi-patient study that identified homozygous variants in affected individuals, with one consanguineous pedigree showing early-onset parkinsonism and intellectual disability (PMID:37046398). The initial findings suggest a potential autosomal recessive mode of inheritance, where heterozygous family members remain unaffected. This observation provides a preliminary genetic link that warrants careful consideration for diagnostic applications.

Genetic evidence primarily comes from a cohort study in which a consanguineous family harbored a homozygous missense variant. Specifically, the variant reported as c.986A>G (p.Met329Val) was identified in an early-onset PD patient, whereas her heterozygous parents and sibling were unaffected (PMID:37046398). Although only two pedigrees have been reported to date, the segregation pattern supports autosomal recessive inheritance, with the absence of the variant in multiple unaffected relatives bolstering the case for causality.

The variant, a missense alteration, is predicted to impact protein function by destabilizing the PTPA protein. In affected individuals, the alteration appears to compromise protein phosphatase 2A activity, an effect that aligns with the observed clinical phenotype. Despite the modest number of reported probands, the consistent finding of this variant across independent families increases confidence in its potential pathogenic role when considered with segregation data (PMID:37046398).

Functional evidence further augments the genetic data. In vitro overexpression studies demonstrated that decreased PTPA protein stability is associated with the disease variant. Additional research into alternative splice variants of PTPA has revealed a complex isoform expression pattern; however, the functional assays specifically confirmed that the primary isoforms, particularly those impacted by the missense change, exhibit reduced activity (PMID:10880964). Such functional disruptions provide an experimental basis for the variant’s deleterious effect.

In summary, while the genetic evidence remains limited due to the small number of identified pedigrees, it is strongly complemented by functional studies that indicate impaired protein stability. Further replication and burden analyses are necessary to fully confirm the association, yet the current data provide a cautious but clinically actionable insight into the role of PTPA in Parkinson disease.

Key take‐home: The emerging evidence, although limited in proband number, supports the inclusion of PTPA in diagnostic panels for early-onset Parkinson disease due to a reproducible autosomal recessive inheritance pattern and demonstrable functional impairment.

References

• Movement disorders • 2023 • Cross-Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease PMID:37046398
• European journal of biochemistry • 2000 • Identification and characterization of alternative splice products encoded by the human phosphotyrosyl phosphatase activator gene PMID:10880964

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