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 language | English |
|---|---|
| Pages (from-to) | 1619-1622 |
| Number of pages | 4 |
| Journal | Human Mutation |
| Volume | 34 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2013 |
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Keywords
- Complex III deficiency
- Encephalopathy
- Lactic acidosis
- LYRM7
- MZM1
- Yeast model
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity. / Invernizzi, Federica; Tigano, Marco; Dallabona, Cristina; Donnini, Claudia; Ferrero, Ileana; Cremonte, Maurizio; Ghezzi, Daniele; Lamperti, Costanza; Zeviani, Massimo.
In: Human Mutation, Vol. 34, No. 12, 12.2013, p. 1619-1622.Research output: Contribution to journal › Article
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TY - JOUR
T1 - A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy, Lactic Acidosis, and Severe Reduction of Mitochondrial Complex III Activity
AU - Invernizzi, Federica
AU - Tigano, Marco
AU - Dallabona, Cristina
AU - Donnini, Claudia
AU - Ferrero, Ileana
AU - Cremonte, Maurizio
AU - Ghezzi, Daniele
AU - Lamperti, Costanza
AU - Zeviani, Massimo
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Complex III deficiency
KW - Encephalopathy
KW - Lactic acidosis
KW - LYRM7
KW - MZM1
KW - Yeast model
UR - http://www.scopus.com/inward/record.url?scp=84887613215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887613215&partnerID=8YFLogxK
U2 - 10.1002/humu.22441
DO - 10.1002/humu.22441
M3 - Article
C2 - 24014394
AN - SCOPUS:84887613215
VL - 34
SP - 1619
EP - 1622
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 12
ER -