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SPG7

MIM.602783 16q24.3

Friday 27 January 2006

SPG7 encodes a nuclear-encoded mitochondrial metalloprotease protein termed paraplegin.

Pathology

- germline SPG7 mutations in SPG7-associated hereditary spastic paraplegia

  • autosomal recessive hereditary pure spastic paraplegia
  • linkage and subsequent mutation analysis revealed large deletions in SPG7

- Muscle biopsies from the autosomal recessive form of patients with hereditary spastic paraplegia revealed histochemical signs of a mitochondrial disorder, namely RRFs, COX-negative fibres and succinate dehydrogenase-positive hyperintense fibres.

- Owing to the homology with a yeast mitochondrial ATPase with both proteolytic and chaperone-like activities, it has been suggested that this form of hereditary spastic paraplegia could be a neurodegenerative disorder due to OXPHOS deficiency, attributing a putative function in the assembly or import of respiratory chain subunits or cofactors to paraplegin.

m-AAA protease

An autosomal recessive form of the disease is caused by mutations in paraplegin, which is a conserved subunit of the ubiquitous and ATP-dependent m-AAA protease in mitochondria.

The m-AAA protease carries out protein quality control in the inner membrane of the mitochondria, suggesting a pathogenic role of misfolded proteins in HSP.

The m-AAA protease regulates ribosome assembly and translation within mitochondria by controlling proteolytic maturation of a ribosomal subunit. Here, we will discuss implications of the dual role of the m-AAA protease in protein activation and degradation for mitochondrial dysfunction and axonal degeneration.

See also

- hereditary spastic paraplegias

  • SPG7-associated hereditary spastic paraplegia

References

- Rugarli EI, Langer T. Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia. Trends Mol Med. 2006 Jun;12(6):262-9. PMID: 16647881

- Shoubridge EA. Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet. 2001 Oct 1;10(20):2277-84. PMID: 11673411

- Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001 May;2(5):342-52. PMID: 11331900