Journal
HUMAN MUTATION
Volume 34, Issue 12, Pages 1619-1622Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.22441
Keywords
LYRM7; MZM1; complex III deficiency; encephalopathy; lactic acidosis; yeast model
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Funding
- Telethon Italy [GGP11011, GPP10005]
- Fondazione CARIPLO [2011/0526]
- Italian Ministry of Health [GR2010-2316392]
- Fondazione Pierfranco e Luisa Mariani
- Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
- MRC [MC_UP_1002/1] Funding Source: UKRI
- Medical Research Council [MC_UP_1002/1] Funding Source: researchfish
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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 mzm1 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. Published 2013 Wiley Periodicals, Inc.
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