Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease

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...

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Bibliographic Details
Published in:Cell 1998-06, Vol.93 (6), p.973-983
Main Authors: Casari, Giorgio, De Fusco, Maurizio, Ciarmatori, Sonia, Zeviani, Massimo, Mora, Marina, Fernandez, Patricio, De Michele, Giuseppe, Filla, Alessandro, Cocozza, Sergio, Marconi, Roberto, Dürr, Alexandre, Fontaine, Bertrand, Ballabio, Andrea
Format: Article
Language:English
Subjects:
Adult
Amino Acid Sequence
ATPases Associated with Diverse Cellular Activities
Cell Nucleus - genetics
Chromosome Deletion
Chromosomes, Human, Pair 16 - genetics
Cloning, Molecular
DNA, Complementary - genetics
Female
Fetus
Frameshift Mutation - genetics
Humans
Italy
Male
Metalloendopeptidases - genetics
Mitochondria - enzymology
Molecular Sequence Data
Muscle, Skeletal - pathology
Oxidative Phosphorylation
Pedigree
RNA, Messenger - analysis
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Spastic Paraplegia, Hereditary - enzymology
Spastic Paraplegia, Hereditary - genetics
Spastic Paraplegia, Hereditary - pathology
Yeasts - enzymology
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81203-9