A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.

TitleA homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.
Publication TypeJournal Article
Year of Publication2013
AuthorsInvernizzi, F, Tigano, M, Dallabona, C, Donnini, C, Ferrero, I, Cremonte, M, Ghezzi, D, Lamperti, C, Zeviani, M
JournalHum Mutat
Volume34
Issue12
Pagination1619-22
Date Published2013 Dec
ISSN1098-1004
KeywordsAcidosis, Lactic, Amino Acid Sequence, Brain, DNA Mutational Analysis, Electron Transport Complex III, Enzyme Activation, Female, Homozygote, Humans, Infant, Magnetic Resonance Imaging, Mitochondrial Encephalomyopathies, Mitochondrial Proteins, Molecular Chaperones, Molecular Sequence Data, Mutation, Pedigree, Saccharomyces cerevisiae, Sequence Alignment
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.

DOI10.1002/humu.22441
Alternate JournalHum. Mutat.
Citation Key10.1002/humu.22441
PubMed ID24014394
PubMed Central IDPMC4028993
Grant ListGGP11011 / / Telethon / Italy