Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.
Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.
Tiranti
V
V
Istituto Nazionale Neurologico, Divisione di Biochimica e Genetica, 20133 Milano, Italy.
Hoertnagel
K
K
Carrozzo
R
R
Galimberti
C
C
Munaro
M
M
Granatiero
M
M
Zelante
L
L
Gasparini
P
P
Marzella
R
R
Rocchi
M
M
Bayona-Bafaluy
M P
MP
Enriquez
J A
JA
Uziel
G
G
Bertini
E
E
Dionisi-Vici
C
C
Franco
B
B
Meitinger
T
T
Zeviani
M
M
D000818:Animals; D002459:Cell Fusion / Q000235:genetics; D002460:Cell Line; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D006224:Cricetinae; D030401:Cytochrome-c Oxidase Deficiency; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D006822:Hybrid Cells; D017404:In Situ Hybridization, Fluorescence; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012234:Rho Factor / Q000235:genetics; D016615:Telomere / Q000235:genetics
D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012234:Rho Factor; C092928:Surf-1 protein; D003576:Electron Transport Complex IV