A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.

Download Full-text

A novel recurrent mitochondrial DNA mutation inND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.31565 ◽

2007 ◽

Vol 143A (1) ◽

pp. 33-41 ◽

Cited By ~ 68

Author(s):

Emmanuelle Sarzi ◽

Michael D. Brown ◽

Sophie Lebon ◽

Dominique Chretien ◽

Arnold Munnich ◽

...

Keyword(s):

Mitochondrial Dna ◽

Complex I ◽

Leigh Syndrome ◽

Mitochondrial Dna Mutation ◽

Dna Mutation ◽

Complex I Deficiency

Download Full-text

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104891 ◽

2017 ◽

Vol 55 (1) ◽

pp. 21-27 ◽

Cited By ~ 16

Author(s):

Kalliopi Sofou ◽

Irenaeus F M de Coo ◽

Elsebet Ostergaard ◽

Pirjo Isohanni ◽

Karin Naess ◽

...

Keyword(s):

Complex I ◽

Mitochondrial Disorder ◽

Mitochondrial Diseases ◽

Leigh Syndrome ◽

Central Nervous System Disease ◽

Genetic Defects ◽

System Disease ◽

Ocular Manifestations ◽

Complex I Deficiency ◽

Mitochondrial Atp Synthase

BackgroundLeigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.ObjectiveWe aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.MethodsWe studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.ResultsWe found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.ConclusionOur study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.

Download Full-text