A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.
Mutations in the SPG7 gene, encoding the mitochondrial protein paraplegin, were the first to be identified in autosomal recessive hereditary spastic paraplegia (ARHSP). Four different SPG7 mutations have been described so far in association with both pure and complicated HSP phenotypes. Muscle biopsies from the most severely affected patients have shown histological evidence of an oxidative phosphorylation defect. We identified six ARHSP kindreds, in whom linkage to SPG7 could not be excluded, and 29 sporadic spastic paraplegia patients. The 17 exons and flanking regions of the SPG7 gene were screened for mutations using a combination of single-stranded conformation polymorphism (SSCP) analysis and sequencing. Three patients were found to carry compound heterozygous SPG7 mutations, comprising five novel and one previously described mutation. Muscle biopsies from two SPG7 mutation patients did not show any histological evidence of an oxidative phosphorylation defect. However, biochemical analysis revealed a reduction in citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts, suggesting that either a primary or a secondary defect of respiratory chain function may play an important role in the pathogenesis of the disease.
Wilkinson
Philip A
PA
Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK.
Crosby
Andrew H
AH
Turner
Christopher
C
Bradley
Lloyd J
LJ
Ginsberg
Lionel
L
Wood
Nicholas W
NW
Schapira
Anthony H
AH
Warner
Thomas T
TT
D000074183:ATPases Associated with Diverse Cellular Activities; D000328:Adult; D001921:Brain / Q000473:pathology; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010264:Paraplegia / Q000235:genetics* / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational
D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities