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

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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 (LSCOX), 6 patients classified as Leigh‐like (LLCOX) cases, and 16 patients classified as non‐LSCOX cases. Frameshift, stop, and splice mutations of SURF‐1 were detected in 18 of 24 (75%) of the LSCOX cases. No mutations were found in the LLCOX and non‐LSCOX 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 LSCOX, although a proportion of LSCOX 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 LSCOX, a common subtype of Leigh syndrome. Ann Neurol 1999;46:161–166