ERLIN2 – Hereditary Spastic Paraplegia 18

Hereditary Spastic Paraplegia 18 (SPG18) is a neurodegenerative disorder characterized by progressive lower limb spasticity and neurodevelopmental complications. The ERLIN2 gene encodes an endoplasmic reticulum lipid‐raft protein involved in inositol 1,4,5‐trisphosphate receptor (IP3R) ubiquitination and ER homeostasis. Biallelic loss‐of‐function variants cause AR SPG18, while monoallelic missense variants produce AD pure or complicated HSP ([PMID:38607533]).

Genetically, SPG18 exhibits both autosomal recessive and autosomal dominant inheritance modes. Recessive cases carry homozygous or compound heterozygous LoF alleles (e.g., c.367G>T (p.Glu123Ter), c.303T>A (p.Tyr101Ter)) leading to juvenile primary lateral sclerosis phenotypes. Dominant pedigrees have segregated heterozygous missense variants in multiple kindreds, notably c.386G>C (p.Ser129Thr) in two European families ([PMID:29528531]) and c.212T>C (p.Val71Ala) in a Chinese four‐generation pedigree with seven affected relatives ([PMID:37752894]).

The variant spectrum spans missense changes in conserved residues and canonical splice‐site disruptions. Missense alleles cluster in the SPFH domain (e.g., p.Ser129Thr, p.Val71Ala) and impair ERLIN2 function without gross oligomerization defects ([PMID:38607533]). Recurrent AR alleles include splice junction mutations such as c.237-2A>G that trigger nonsense‐mediated decay in juvenile PLS ([PMID:23109145]).

Functional studies support a loss‐of‐function and ER stress mechanism. Overexpression of p.Val71Ala in patient iPSC‐derived neurons recruits RNF213 to degrade IP3R1, reducing intracellular calcium, activating ER stress–mediated apoptosis, and impairing MAPK signaling ([PMID:40225166]). The T65I mutation disrupts IP3R ubiquitination and phosphatidylinositol 3‐phosphate binding by the erlin1/2 complex, highlighting ERLIN2’s key role in ER homeostasis ([PMID:30135210]).

Mechanistically, ERLIN2 variants lead to defective IP3R turnover, calcium dysregulation, and ER stress, contributing to axonopathy in upper motor neurons. Both AR and AD alleles converge on impaired ER function but differ in residual protein activity: LoF alleles ablate function, whereas dominant missense variants exert partial loss with stress‐inducing effects.

Collectively, multiple unrelated AR and AD pedigrees, segregation in nine kindreds, and concordant cellular models justify a Strong clinical validity classification. Functional data reach a Moderate level under ClinGen criteria, supporting a haploinsufficiency/ER stress mechanism. ERLIN2 sequencing is clinically useful for diagnosing SPG18 across inheritance modes.

Key Take‐home: ERLIN2 testing enables robust SPG18 diagnosis; variant interpretation should consider both AR LoF and AD missense alleles with ER stress readouts.

References

• Neurological sciences • 2024 • Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family. [PMID:38607533]
• Annals of clinical and translational neurology • 2023 • A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family. [PMID:37752894]
• European journal of neurology • 2018 • A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia. [PMID:29528531]
• Human mutation • 2023 • Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models. [PMID:40225166]
• 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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