title: The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy.
abstract: A novel mitochondrial DNA (mtDNA) transition (3733G-->A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G-->A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex I to rotenone inhibition. We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON.
authors.affiliation: Dipartimento di Scienze Neurologiche, Università di Bologna, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Laura
authors.initials: L
authors.lastname: Bucchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Rengo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Achilli
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lugaresi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.forename: Bruno
authors.initials: B
authors.lastname: Barbiroli
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Dotti
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.forename: Agostino
authors.initials: A
authors.lastname: Baruzzi
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D005192:Family Health; D005260:Female; D005292:Ferricyanides / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000473:pathology / Q000648:ultrastructure; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D009243:NAD / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009778:Occipital Lobe / Q000000981:diagnostic imaging; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D011877:Radionuclide Imaging; D012402:Rotenone / Q000494:pharmacology; D020539:Sequence Analysis, Protein / Q000379:methods; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; D005292:Ferricyanides; D018698:Glutamic Acid; D008239:Lysine; D009243:NAD; D009245:NADH Dehydrogenase; D012402:Rotenone; D013385:Succinate Dehydrogenase; C007931:hexacyanoferrate III; C515075:NADH dehydrogenase subunit 1, human