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HS1BP3 – Parkinson Disease

The association between variants in HS1BP3 (HGNC:24979) and Parkinson disease (MONDO_0005180) has been critically evaluated across several studies. Early case‐control investigations, such as the study reporting the DRD3 Ser9Gly and HS1BP3 Ala265Gly variants, failed to demonstrate significant differences in variant frequency between Parkinson disease cases and controls (PMID:19524641).

Subsequent multi‐patient studies focusing on related phenotypes, notably essential tremor, identified the HS1BP3 variant c.828C>G (p.Ala265Gly) in familial cohorts; however, its occurrence in individuals with Parkinson disease was infrequent and did not reach statistical significance (PMID:16211613).

In detailed family studies that screened for HS1BP3 Ala265Gly, the variant was detected in several family members, yet it did not co‐segregate with Parkinson disease, essential tremor, or other related neurological conditions (PMID:17353387). This lack of segregation undermines its potential causal role in the pathogenesis of Parkinson disease.

Functional assessments conducted in these studies have also failed to provide compelling evidence that the HS1BP3 A265G alteration significantly disrupts protein function or alters biological pathways implicated in Parkinson disease. The experimental data, therefore, do not support a mechanistic link between HS1BP3 dysfunction and Parkinson disease etiology.

Overall, the genetic and experimental evidence converges to dispute a robust association between HS1BP3 variants and Parkinson disease. Despite multiple investigations including case–control analyses and familial studies, neither the frequency of the variant nor its functional impact has provided sufficient evidence to establish causation.

Key take‑home sentence: Current evidence does not support the clinical utility of screening HS1BP3 for Parkinson disease, as the variant c.828C>G (p.Ala265Gly) shows inconsistent association, absence of segregation, and limited functional effects.

References

  • Neuroscience letters • 2009 • DRD3 Ser9Gly and HS1BP3 Ala265Gly are not associated with Parkinson disease PMID:19524641
  • Movement disorders : official journal of the Movement Disorder Society • 2006 • HS1-BP3 gene variant is common in familial essential tremor PMID:16211613
  • Archives of neurology • 2007 • A family with Parkinson disease, essential tremor, bell palsy, and parkin mutations PMID:17353387

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Multiple independent studies (PMID:19524641, PMID:17353387) have consistently failed to demonstrate a significant association between HS1BP3 variation and Parkinson disease, with no reliable segregation observed among affected relatives (0 relatives) and inconsistent variant frequency across cohorts (PMID:16211613).

Genetic Evidence

Disputed

The HS1BP3 variant c.828C>G (p.Ala265Gly), although reported in several familial studies, did not segregate with Parkinson disease and lacks statistical support in case–control analyses.

Functional Evidence

Limited

Functional assays and experimental data have not demonstrated significant alterations in protein function or biological pathways relevant to Parkinson disease, limiting the evidence for a mechanistic role of HS1BP3 variants in disease pathogenesis (PMID:17353387).