NOVÁ MISSENSE MUTACE 574C>T V GENU SURF1 –BIOCHEMICKÁ A MOLEKULÁRNĚ GENETICKÁ STUDIEU SEDMI DĚTÍ S LEIGHOVÝM SYNDROMEM

A Novel Missense Mutation 574C>T in SURF1 Gene - Biochemicaland Molecular Studies in Seven Children with Leigh Disease

Background.
Leigh disease, subacute necrotizing encephalopathy, is a serious mitochondrial disorder of energy--providing metabolism. Clinical presentation usually starts in infancy as a progressive neurodegenerative disorderwith retardation and regression of psychomotor development. The most common form of the disease is associatedwith deficiency of the cytochrome c oxidase (COX) due to SURF1 gene mutations. SURF1 encodes an innermitochondrial membrane protein involved in the biogenesis and assembly of COX complex.Methods and Results. The activities of mitochondrial respiratory chain complexes were determined spectrophotometricallyin isolated lymphocytes, platelets, muscle mitochondria and cultured fibroblasts. Generalised decreaseof COX activity was found in 7 children with typical symptoms of Leigh disease. Two-dimensional electrophoresisof mitochondrial proteins showed altered assembly pattern of COX. As demonstrated by Western blot analysis ofmitochondria or mitoplasts with anti-hSurf1 antibodies (gift fromDr. E. A. Shoubridge), the Surf1 protein was absentin all 5 investigated patients. Molecular analyses in the 7 patients revealed the presence of mutations in the SURF1gene – six patients harboured previously described SURF1 mutations, a new mutation 574C>T was found in onepatient.Conclusions. The co-operation among the patient’s families, clinicians and specialised laboratories is essentialfor the diagnostic of mitochondrial disorders. The treatment of Leigh syndrome is only symptomatic and the prognosisof the disease is unfavourable. The diagnostics on biochemical andmolecular level is necessary for genetic counsellingand prenatal diagnosis in affected families.

Key words:
Leigh syndrome, SURF1 gene, Surf1 protein, cytochrome c oxidase.