A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity

Federica Invernizzi, Marco Tigano, Cristina Dallabona, Claudia Donnini, Ileana Ferrero, Maurizio Cremonte, Daniele Ghezzi, Costanza Lamperti, Massimo Zeviani

Research output: Contribution to journalArticlepeer-review

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 mzm1D25N 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. We report the first patient affected by an infantile mitochondrial disease caused by a mutation in LYRM7. The patient displayed severe complex III deficiency, associated with early-onset lactic acidosis and rapidly progressive encephalopathy.

Original languageEnglish
Pages (from-to)1619-1622
Number of pages4
JournalHuman Mutation
Volume34
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • Complex III deficiency
  • Encephalopathy
  • Lactic acidosis
  • LYRM7
  • MZM1
  • Yeast model

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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