title: A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.
abstract: Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1Δ yeast strain, the expression of a mzm1(D25N) mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe-S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy.
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Marco
authors.initials: M
authors.lastname: Tigano
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnini
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cremonte
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D014450:Electron Transport Complex III / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D017237:Mitochondrial Encephalomyopathies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C000588844:LYRM7 protein, human; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D014450:Electron Transport Complex III
keywords: LYRM7; MZM1; complex III deficiency; encephalopathy; lactic acidosis; yeast model