Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease.

TitleSpastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease.
Publication TypeJournal Article
Year of Publication1998
AuthorsCasari, 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
JournalCell
Volume93
Issue6
Pagination973-83
Date Published1998 Jun 12
ISSN0092-8674
KeywordsAdult, Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Cell Nucleus, Chromosome Deletion, Chromosomes, Human, Pair 16, Cloning, Molecular, DNA, Complementary, Female, Fetus, Frameshift Mutation, Humans, Italy, Male, Metalloendopeptidases, Mitochondria, Molecular Sequence Data, Muscle, Skeletal, Oxidative Phosphorylation, Pedigree, RNA, Messenger, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Spastic Paraplegia, Hereditary, Yeasts
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.

DOI10.1016/s0092-8674(00)81203-9
Alternate JournalCell
Citation Key10.1016/s0092-8674(00)81203-9
PubMed ID9635427
Grant List767 / / Telethon / Italy
TGM06S01 / / Telethon / Italy
TGM97000 / / Telethon / Italy