title: Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.
abstract: Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases. Frameshift, stop, and splice mutations of SURF-1 were detected in 18 of 24 (75%) of the LS(COX) cases. No mutations were found in the LL(COX) and non-LS(COX) group of patients. Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically associated with LS(COX), although a proportion of LS(COX) cases must be the result of abnormalities in genes other than SURF-1. SURF-1 is the first nuclear gene to be consistently mutated in a major category of respiratory chain defects. DNA analysis can now be used to accurately diagnose LS(COX), a common subtype of Leigh syndrome.
authors.affiliation: Istituto Nazionale Neurologico C Besta, Milano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tiranti
authors.forename: M
authors.initials: M
authors.lastname: Jaksch
authors.forename: S
authors.initials: S
authors.lastname: Hofmann
authors.forename: C
authors.initials: C
authors.lastname: Galimberti
authors.forename: K
authors.initials: K
authors.lastname: Hoertnagel
authors.forename: L
authors.initials: L
authors.lastname: Lulli
authors.forename: P
authors.initials: P
authors.lastname: Freisinger
authors.forename: L
authors.initials: L
authors.lastname: Bindoff
authors.forename: K D
authors.initials: KD
authors.lastname: Gerbitz
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
authors.forename: G
authors.initials: G
authors.lastname: Uziel
authors.forename: M
authors.initials: M
authors.lastname: Zeviani
authors.forename: T
authors.initials: T
authors.lastname: Meitinger
mesh_terms: D002675:Child, Preschool; D030401:Cytochrome-c Oxidase Deficiency; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009132:Muscles / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C092928:Surf-1 protein; D003576:Electron Transport Complex IV