Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency

Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with def iciency of cytochrome c oxidase (COX), the terminal component of the mitoch ondrial respiratory chain. To investigate to what extent SURF-1 is responsi ble for human disorders because of COX deficiency, we undertook sequence an alysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defe ctive patients classified as having typical Leigh syndrome (LSCOX), 6 patie nts classified as Leigh-like (LLCOX) cases, and 16 patients classified as n on-LSCOX cases. Frameshift, stop, and splice mutations of SURF-1 were detec ted in 18 of 24 (75%) of the LSCOX cases. No mutations were found in the LL COX smd non-LSCOX group of patients. Rescue of the COX phenotype was observ ed in transfected cells from patients harboring SURF-1 mutations, but not i n transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically a ssociated with LSCOX, although a proportion of LSCOX cases must be the resu lt 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 d efects. DNA analysis can now be used to accurately diagnose LSCOX, a common subtype of Leigh syndrome.