title: Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy.
abstract: Isolated Complex I (CI) deficiency, the most frequent cause of mitochondrial disease, is a clinically and genetically heterogeneous condition. Complex I is a giant multiheteromeric enzyme composed of seven ND subunits encoded by mitochondrial DNA (mtDNA) genes, and at least 38 subunits encoded by nuclear genes. To establish the contribution to human mitochondrial encephalopathy of ND versus nuclear gene mutations, we have been undertaking a systematic analysis of CI genes in a cohort of 46 adult and paediatric patients with biochemically defined CI defect. Sequence analysis of the entire mtDNA let us identify six patients with mutations in ND genes. The clinical presentations varied, from infantile Leigh syndrome, to childhood MELAS, to adult-onset encephalopathic syndromes of variable severity. Three of the mutations were not previously reported (3481G > A, 14600G > A and 13063G > A, in ND1, ND6 and ND5 genes, respectively) and were further investigated in mutant transmitochondrial cybrids. Tight correlation between mutation load and decrease in CI activity was observed in each of the three mutant cybrid lines, supporting the pathogenic role of the novel mutations. Structural studies on mutant cybrids showed impaired assembly or reduced stability of the holoenzyme complex. In our experience ND gene mutations are relatively common in CI-defective mitochondrial encephalopathy of both children and adults.
authors.affiliation: Unit of Molecular Neurogenetics, Neurological Institute C. Besta Foundation IRCCS, via Libero Temolo 4, 20126 Milano, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Carolina Fischinger-Moura
authors.initials: CF
authors.lastname: de Souza
authors.forename: Laura
authors.initials: L
authors.lastname: Farina
authors.forename: Franco
authors.initials: F
authors.lastname: Carrara
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.forename: Carlo
authors.initials: C
authors.lastname: Antozzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Confalonieri
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sanseverino
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D013045:Species Specificity
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I