title: Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease.
abstract: Hereditary spastic paraplegia (HSP) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. We found that patients from a chromosome 16q24.3-linked HSP family are homozygous for a 9.5 kb deletion involving a gene encoding a novel protein, named Paraplegin. Two additional Paraplegin mutations, both resulting in a frameshift, were found in a complicated and in a pure form of HSP. Paraplegin is highly homologous to the yeast mitochondrial ATPases, AFG3, RCA1, and YME1, which have both proteolytic and chaperon-like activities at the inner mitochondrial membrane. Immunofluorescence analysis and import experiments showed that Paraplegin localizes to mitochondria. Analysis of muscle biopsies from two patients carrying Paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in HSP-type disorders.
authors.affiliation: Telethon Institute of Genetics and Medicine, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Casari
authors.forename: M
authors.initials: M
authors.lastname: De Fusco
authors.forename: S
authors.initials: S
authors.lastname: Ciarmatori
authors.forename: M
authors.initials: M
authors.lastname: Zeviani
authors.forename: M
authors.initials: M
authors.lastname: Mora
authors.forename: P
authors.initials: P
authors.lastname: Fernandez
authors.forename: G
authors.initials: G
authors.lastname: De Michele
authors.forename: A
authors.initials: A
authors.lastname: Filla
authors.forename: S
authors.initials: S
authors.lastname: Cocozza
authors.forename: R
authors.initials: R
authors.lastname: Marconi
authors.forename: A
authors.initials: A
authors.lastname: Dürr
authors.forename: B
authors.initials: B
authors.lastname: Fontaine
authors.forename: A
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000328:Adult; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000235:genetics; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005333:Fetus; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D010085:Oxidative Phosphorylation; D010375:Pedigree; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015003:Yeasts / Q000201:enzymology
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities