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RHOT2 and Parkinson Disease

The association between RHOT2 and Parkinson disease has been evaluated in multi‐patient genetic studies with conflicting results. In one candidate gene study, exome sequencing of 26 dominant late onset Parkinson disease families identified RHOT2 among sixteen novel candidate genes with 28 disrupting variants reported in the discovery phase (PMID:34148545). However, subsequent large‑scale analyses utilizing whole‑genome sequencing and genotyping data failed to confirm an association between RHOT2 genetic variation and Parkinson disease risk or age at onset (PMID:32948353).

Functional assessments have provided moderate support for a role of RHOT2 in the pathogenesis of Parkinson disease. Experimental studies have shown that RHOT2, a key component in mitochondrial dynamics, participates in the recognition of substrates by Parkin—one of the central proteins in the mitophagy pathway (PMID:27605430). The biochemical data indicate that alterations in RHOT2 function may contribute to mitochondrial dysregulation, although the genetic evidence remains limited and conflicting. This discrepancy underlines the need for further studies to clarify the clinical utility of RHOT2 variation in diagnostic settings.

References

  • Molecular neurodegeneration • 2021 • Identification of sixteen novel candidate genes for late onset Parkinson's disease PMID:34148545
  • Neurobiology of aging • 2021 • The role of RHOT1 and RHOT2 genetic variation on Parkinson disease risk and onset PMID:32948353
  • Scientific reports • 2016 • Structural insights into Parkin substrate lysine targeting from minimal Miro substrates PMID:27605430

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

An initial candidate study identified RHOT2 variants in 26 dominant PD families with 28 disrupting variants reported (PMID:34148545), but subsequent large‑scale analyses failed to support an association with PD risk or age at onset (PMID:32948353).

Genetic Evidence

Limited

While the candidate gene study reported deleterious variants in RHOT2, the lack of corroborative segregation data and negative replication in larger cohorts constrains the genetic evidence.

Functional Evidence

Moderate

Functional studies indicate that RHOT2 is implicated in mitochondrial dynamics and acts as a substrate for Parkin, reinforcing a potential mechanistic link to Parkinson disease pathogenesis (PMID:27605430).