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

Hum Mutat. 2013 Dec;34(12):1619-22. doi: 10.1002/humu.22441. Epub 2013 Sep 23.


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.

Keywords: LYRM7; MZM1; complex III deficiency; encephalopathy; lactic acidosis; yeast model.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / diagnosis
  • Acidosis, Lactic / genetics*
  • Acidosis, Lactic / 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
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Encephalomyopathies / metabolism*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics*
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Sequence Alignment


  • LYRM7 protein, human
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Electron Transport Complex III

Supplementary concepts

  • Mitochondrial encephalopathy