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FB2026_01
,
released March 12, 2026
This report describes spastic paraplegia 31, which shows autosomal dominant inheritance. The human gene implicated in this disease is REEP1, an ER protein required for correct formation of ER networks. There is a highest-ranking ortholog of human REEP1 in Drosophila, ReepA, although there are also two ReepA paralogs in Drosophila and six REEP family proteins in humans. Several alleles have been generated of ReepA, including amorphic alleles, fluorescently tagged alleles, and alleles carrying RNAi targeting constructs.
The human gene Hsap\REEP1 has been introduced into flies.
Overexpression of both human Hsap\REEP1 and fly ReepA cause a reduction in cisternal ER structures (ER sheets), whereas ReepA loss-of-function mutants show an increase in cisernal structures and reduction in tubular (peripheral) ER complexity. ReepA is upregulated in older flies and flies exposed to ER stress by heat-shock and tunicamycin treatment. ReepA mutant flies fail to trigger activations of aspects of the unfolded protein response to ER stress.
[updated Jan. 2020 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from MIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT; SPG31](https://omim.org/entry/610250)
[RECEPTOR EXPRESSION-ENHANCING PROTEIN 1; REEP1](https://omim.org/entry/609139)
All SPG31 patients studied by Zuchner et al. 2016 (pubmed:16565863) had typical signs of spastic paraplegia mainly characterized by proximal weakness of the lower extremities with brisk reflexes and spastic gait abnormalities. The upper extremities showed normal tone and only very mild weakness of the small hand muscles. The sensory system was not involved. No additional neurologic symptoms were present that suggested cerebellar or visual involvement. Mutation in the REEP1 gene can also cause distal hereditary motor neuronopathy, type V (HMN5B; MIM:614751). Some patients with REEP1 mutations show overlapping signs of HMN5B and SPG31, indicating that there is a phenotypic spectrum of manifestations associated with REEP1 mutations. [adapted from MIM:610250, 2020.01.28]
Hereditary spastic paraplegias have been associated with more than 40 different genetic loci, but well over 50% of HSP patients harbor pathogenic mutations in 1 of just 3 genes: spastin (SPG4, also known as SPAST), atlastin-1 (SPG3A, also known as ATL1), or receptor expression enhancing protein 1 (REEP1, also known as SPG31). (Adapted from Park et al. 2010, pubmed:20200447.)
At present, 56 pathogenic REEP1 variants have been reported. Disease-causing variants in REEP1 are predominantly truncating mutations suspected to trigger the nonsense-mediated mRNA decay, and the pathogenic mechanism is generally thought to be haploinsufficiency. A few pathogenic missense variants affecting highly conserved amino acids of REEP1 have been identified, as well, and 3′-UTR variants are speculated to be pathogenic by affecting a miRNA-binding site. (From Toft et al. 2019, pubmed:30637453.)
Beetz et al. 2008 (pubmed:18321925) postulate haploinsufficiency as the main molecular genetic mechanism of REEP1 pathogenesis. [adapted from MIM:610250, 2020.01.28]
REEP1 modifies ER architecture, is implicated in ER stress response, and has a role in Lipid Droplet (LD) biogenesis. (Adapted from Napoli et al. 2019 and references therein, FBrf0244226.)
Many to many: 3 human genes to 2 Drosophila genes.
Drosophila genes ReepA and CG5539 are both high-ranking orthogs of human genes Hsap\REEP1, REEP2, and REEP3. In a 2014 publication (FBrf0226832), Appocher and colleagues concluded that ReepA was the closest ortholog of Hsap\REEP1.