ERLIN2 – Hereditary Spastic Paraplegia

The association between ERLIN2 and hereditary spastic paraplegia (HSP) has been supported by multiple independent studies that identified both autosomal dominant and recessive mutations, with a preponderance of evidence in autosomal dominant pedigrees. Several studies have documented heterozygous missense variants that segregate with a pure HSP phenotype in multi‑generational families, where affected individuals present with lower limb weakness and spasticity (PMID:32094424, PMID:37752894). In one study, a Korean family exhibited a novel missense mutation, c.452C>T (p.Ala151Val), which was detected by whole‑exome sequencing and validated by segregation analysis in multiple affected relatives (PMID:32094424).

Additional case series and pedigree analyses have further reinforced the genetic evidence by reporting similar autosomal dominant variants in ERLIN2, with functional prediction scores supporting their pathogenicity. The cumulative genetic data, inclusive of recurrent and independent observations across distinct populations, indicate that ERLIN2 variants can disrupt protein function through mechanisms involving endoplasmic reticulum (ER) stress and abnormal intracellular calcium homeostasis. These findings are bolstered by experimental evidence that demonstrates altered ER morphology and perturbed ubiquitination of key substrates in cellular models, aligning with the clinical manifestations observed in patients (PMID:30135210).

Functional studies using patient‑derived cells and in vitro models have provided moderate supportive evidence, demonstrating that loss of ERLIN2 function leads to ER stress and impaired protein degradation. Such experimental data are consistent with the clinical phenotype of HSP and offer mechanistic insights into disease pathogenesis. These studies also suggest that the pathogenicity of ERLIN2 variants may be mediated by both haploinsufficiency and dominant‑negative effects, further complicating the inheritance spectrum.

Collectively, the integration of robust genetic evidence from multiple affected families and confirmatory functional studies results in a strong gene‑disease association between ERLIN2 and hereditary spastic paraplegia. While additional data exist that elaborate the complexity of inheritance patterns and variable expressivity, the available evidence rigorously supports the clinical utility of assessing ERLIN2 in the diagnostic evaluation of HSP. Clinicians and genetic testing laboratories should consider ERLIN2 mutations, particularly in patients presenting with pure spastic paraplegia, as they offer valuable insights for genetic counseling and patient management.

Key Take‑home sentence: ERLIN2 mutations serve as a strong diagnostic marker for hereditary spastic paraplegia, with both genetic segregation and functional assay data underscoring their clinical relevance.

References

• Scientific Reports • 2020 • An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18) PMID:32094424
• Annals of Clinical and Translational Neurology • 2023 • A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family PMID:37752894
• The Journal of Biological Chemistry • 2018 • The erlin2 T65I mutation inhibits erlin1/2 complex-mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3‑phosphate binding PMID:30135210

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