The SPG7 gene contains 21 exons and encodes for a protein that is approximately 88 kDa in size. Two transcript variants encoding distinct isoforms have been identified for this gene.
The structure of the SPG7 resolved by X-ray crystallography reveals that the protein functions as a hexamer and is structurally most similar to bacterial FtSH proteases. It contains an FtsH-homology protease domain as well as an AAA+ homology ATPase domain. The protein is thought to use ATPase-driven conformational changes to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.[4]
The SPG7 protein is a nuclear-encoded metalloprotease protein that is a member of the AAA protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The SPG7 protein is a transmembrane protein that is located to the inner mitochondrial membrane, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra-mitochondrialproteases that function in mitochondrial protein quality control.
Mutations associated with this gene cause autosomal recessive spastic paraplegia 7, a neurodegenerative disorder that is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG7 mutations have also been associated with other undiagnosed ataxia.[5][6][7]
In model animals, knockdown of spastic paraplegia 7 by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1.[8] It has been shown that an SPG7 variant escapes phosphorylation-regulated processing by AFG3L2 and increases mitochondrial reactive oxygen species generation and is correlated with many clinical phenotypes.[9] Furthermore, SPG7 deficiency is associated with abnormal mitochondrial DNA maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions.[10]
↑Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A (Jun 1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/S0092-8674(00)81203-9. PMID9635427.
↑Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, Dziewas R, Deppe M, Ringelstein EB, Young P (2010). "A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects". Mov. Disord. 25 (4): 413–20. doi:10.1002/mds.22949. PMID20108356.
↑Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A (1998). "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease". Cell. 93 (6): 973–83. doi:10.1016/s0092-8674(00)81203-9. PMID9635427.
Pullman WE, Bodmer WF (Apr 1992). "Cloning and characterization of a gene that regulates cell adhesion". Nature. 356 (6369): 529–32. doi:10.1038/356529a0. PMID1560826.
Koyama K, Emi M, Nakamura Y (Apr 1993). "The cell adhesion regulator (CAR) gene, TaqI and insertion/deletion polymorphisms, and regional assignment to the peritelomeric region of 16q by linkage analysis". Genomics. 16 (1): 264–5. doi:10.1006/geno.1993.1173. PMID8098008.
Pullman WE, Bodmer WF (Feb 1993). "Cloning and characterization of a gene that regulates cell adhesion". Nature. 361 (6412): 564. doi:10.1038/361564c0. PMID8429914.
Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF (1999). "Genomic structure and expression analysis of the spastic paraplegia gene, SPG7". Human Genetics. 105 (1–2): 139–44. doi:10.1007/s004390051076. PMID10480368.
Kremmidiotis G, Gardner AE, Settasatian C, Savoia A, Sutherland GR, Callen DF (Aug 2001). "Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein". Genomics. 76 (1–3): 58–65. doi:10.1006/geno.2001.6560. PMID11549317.
McDermott CJ, Roberts D, Tomkins J, Bushby KM, Shaw PJ (Jun 2003). "Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND)". Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 4 (2): 96–9. doi:10.1080/14660820310012718. PMID14506940.
Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (Mar 2006). "Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia". Neurology. 66 (5): 654–9. doi:10.1212/01.wnl.0000201185.91110.15. PMID16534102.
Warnecke T, Duning T, Schwan A, Lohmann H, Epplen JT, Young P (Jul 2007). "A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation". Neurology. 69 (4): 368–75. doi:10.1212/01.wnl.0000266667.91074.fe. PMID17646629.
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