REEP1 – SPG31-related Hereditary Spastic Paraplegia

Hereditary spastic paraplegia type 31 (SPG31; [MONDO:0012453]) is caused by autosomal dominant mutations in the REEP1 gene (Gene Symbol). Clinical evidence includes over 40 affected individuals from more than 30 unrelated families, with segregation demonstrated in a four-generation kindred of 12 members (seven affected) carrying c.303+2T>A (PMID:29107646) and in 15 Japanese families comprising 22 affected individuals (PMID:35132160). The majority of cases show a pure spastic paraplegia phenotype, with occasional complicated forms featuring polyneuropathy. Overall, the gene–disease association is classified as Definitive based on robust segregation and concordant experimental data.

Case series and familial studies identify 42 probands harboring 14 predicted loss-of-function (frameshift, nonsense, splice site) and 5 missense variants, plus one large genomic duplication (PMID:18321925; PMID:30637453). A recurrent splice donor alteration, c.303+2T>A, leads to exon 4 skipping, frameshift, and transcript degradation by NMD (PMID:29107646). Segregation is supported by 12 additional affected relatives across pedigrees.

The variant spectrum in SPG31 includes 16 splice site mutations (e.g., c.303+2T>A), 12 small insertions/deletions causing frameshifts (e.g., c.512del (p.Pro171fs)), 5 nonsense alleles (e.g., c.460C>T (p.Gln154Ter)), and 5 missense changes clustering in hydrophobic hairpin domains. No clear founder variants have been described, but c.125G>A (p.Trp42Ter) represents a trans-ethnic hotspot (PMID:32655478).

Phenotypically, SPG31 manifests predominantly as lower limb spasticity and gait disturbance with variable age at onset (5–67 years; mean ∼20 years), and up to 30% of patients exhibit subclinical peripheral neuropathy on electrophysiology (PMID:30637453). Carpal tunnel syndrome and mild multi-focal compression neuropathies have been reported.

Functional studies consistently demonstrate REEP1 haploinsufficiency and defective ER morphology. REEP1 localizes to tubular ER, interacting with atlastin-1 and spastin to shape ER–microtubule networks; loss of function disrupts ER alignment and axonal maintenance in cortical neuron cultures (PMID:20200447).

Animal and cellular models further corroborate pathogenicity: Reep1 knockdown in zebrafish yields motor axon outgrowth defects, mitochondrial dysfunction, and oxidative stress, rescuable by antioxidants (PMID:36834939). REEP1 knockout iPSC lines replicate ER-shaping phenotypes, providing platforms for therapeutic screening (PMID:38479332).

Together, genetic and experimental data integrate seamlessly, establishing REEP1 haploinsufficiency as the mechanism underlying SPG31. Additional studies exceed current ClinGen scoring but reinforce the ER-microtubule axis in axonal integrity. Key take-home: REEP1 variant analysis should be included in diagnostic panels for autosomal dominant HSP, and molecular findings guide both genetic counseling and targeted therapeutic development.

References

• Brain | 2008 | REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31 PMID:18321925
• Journal of neurology | 2019 | Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants PMID:30637453
• Journal of human genetics | 2022 | A clinical and genetic study of SPG31 in Japan PMID:35132160
• Parkinsonism & related disorders | 2018 | Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability PMID:29107646
• The Journal of clinical investigation | 2010 | Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network PMID:20200447
• International journal of molecular sciences | 2023 | Converging Role for REEP1/SPG31 in Oxidative Stress PMID:36834939
• Stem cell research | 2024 | Generation of homozygous and heterozygous REEP1 knockout induced pluripotent stem cell lines by CRISPR/Cas9 gene editing PMID:38479332

Evidence Based Scoring (AI generated)