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RTN3 – Alzheimer Disease

The association between RTN3 and Alzheimer disease has been explored in multiple studies. A targeted sequencing study in early‑onset and late‑onset AD cohorts identified several rare heterozygous variants in RTN3, including the coding variant c.116 C>T (p.Thr39Met) (PMID:29356939) that was absent in controls. However, an independent case‑control study in a Northern Irish population found no significant association between RTN3 variants and AD risk (PMID:19669607). These conflicting genetic findings suggest that while RTN3 variants may act as potential modifiers of AD pathology, the overall genetic evidence remains limited.

Complementary functional studies provide moderate support for RTN3’s role in AD pathogenesis. Multiple experiments have shown that RTN3 physically interacts with BACE1 and that altered RTN3 expression modulates BACE1 activity, leading to changes in amyloid‑beta production and neuritic plaque formation (PMID:16965550; PMID:25319692). This experimental evidence, despite not fully reconciling the inconsistent genetic data, highlights a plausible mechanism impacting amyloid metabolism. Key take‑home sentence: Although genetic associations are conflicting, the functional data underscore RTN3’s biologically relevant role in modulating amyloid‑beta production, supporting its potential utility in diagnostic decision‑making and therapeutic targeting in Alzheimer disease.

References

  • Human Genetics • 2018 • Identification of rare RTN3 variants in Alzheimer's disease in Han Chinese PMID:29356939
  • Neuromolecular Medicine • 2009 • Variation in RTN3 and PPIL2 genes does not influence platelet membrane beta‑secretase activity or susceptibility to Alzheimer's disease in the northern Irish population PMID:19669607
  • The European Journal of Neuroscience • 2006 • Reticulons RTN3 and RTN4‑B/C interact with BACE1 and inhibit its ability to produce amyloid beta‑protein PMID:16965550
  • The Journal of Neuroscience • 2014 • Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition PMID:25319692

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Rare heterozygous variants were identified in AD patients (154 early‑onset and 285 late‑onset cases) (PMID:29356939), but lack of association was observed in a larger Northern Irish cohort (469 AD cases, 347 controls) (PMID:19669607), leading to a limited overall association.

Genetic Evidence

Limited

Genetic evidence is based on the detection of rare variants, including c.116 C>T (p.Thr39Met) in AD patients, but inconsistent replication in independent cohorts reduces the strength of this evidence.

Functional Evidence

Moderate

Multiple functional studies demonstrate that RTN3 interacts with BACE1 and that RTN3 deficiency leads to increased BACE1 activity and amyloid‑beta production (PMID:16965550; PMID:25319692), supporting a moderate level of experimental evidence.