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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.
AuthorsFederica Invernizzi, Marco Tigano, Cristina Dallabona, Claudia Donnini, Ileana Ferrero, Maurizio Cremonte, Daniele Ghezzi, Costanza Lamperti, Massimo Zeviani
JournalHuman mutation (Hum Mutat) Vol. 34 Issue 12 Pg. 1619-22 (Dec 2013) ISSN: 1098-1004 [Electronic] United States
PMID24014394 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.
Chemical References
  • LYRM7 protein, human
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Electron Transport Complex III
Topics
  • Acidosis, Lactic (diagnosis, genetics, metabolism)
  • Amino Acid Sequence
  • Brain (pathology)
  • DNA Mutational Analysis
  • Electron Transport Complex III (metabolism)
  • Enzyme Activation
  • Female
  • Homozygote
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Mitochondrial Encephalomyopathies (diagnosis, genetics, metabolism)
  • Mitochondrial Proteins (chemistry, genetics)
  • Molecular Chaperones (chemistry, genetics)
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Saccharomyces cerevisiae (genetics, metabolism)
  • Sequence Alignment

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