title: Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1.
abstract: We present clinical, neuroimaging, and molecular data on the identification of a new homozygous c.1783A>G (p.Thr595Ala) mutation in NDUFS1 in two inbred siblings with isolated complex I deficiency associated to a progressive cavitating leukoencephalopathy, a clinical and neuroradiological entity originally related to unknown defects of the mitochondrial energy metabolism. In both sibs, the muscle biopsy showed severe reduction of complex I enzyme activity, which was not obvious in fibroblasts. We also observed complex I dysfunction in a Neurospora crassa model of the disease, obtained by insertional mutagenesis, and in patient fibroblasts grown in galactose. Altogether, these results indicate that the NDUFS1 mutation is responsible for the disease and complex I deficiency. Clinical presentation of complex I defect is heterogeneous and includes an ample array of clinical phenotypes. Expanding the number of allelic variants in NDUFS1, our findings also contribute to a better understanding on the function of complex I.
authors.affiliation: Centro de Genética Médica Jacinto Magalhães, Instituto Nacional de Saúde Ricardo Jorge, Porto, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Ferreira
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Castana
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Go
authors.forename: Frank E
authors.initials: FE
authors.lastname: Nargang
authors.forename: Margarida
authors.initials: M
authors.lastname: Duarte
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Videira
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009492:Neurospora crassa / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C487793:NDUFS1 protein, human; D011994:Recombinant Proteins; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I