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

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

Author information

1
Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Neurologico "Carlo Besta", Milan, Italy.

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.

KEYWORDS:

LYRM7; MZM1; complex III deficiency; encephalopathy; lactic acidosis; yeast model

PMID:
24014394
PMCID:
PMC4028993
DOI:
10.1002/humu.22441
[Indexed for MEDLINE]
Free PMC Article
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