Abstract
COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.
| Original language | English |
|---|---|
| Journal | Human Mutation |
| DOIs | |
| Publication status | Accepted/In press - 2017 |
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Keywords
- Complex IV
- COX5A
- Cytochrome c oxidase
- OXPHOS
- Pulmonary arterial hypertension
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. / Baertling, Fabian; Al-Murshedi, Fathiya; Sánchez-Caballero, Laura; Al-Senaidi, Khalfan; Joshi, Niranjan P.; Venselaar, Hanka; van den Brand, Mariël Am; Nijtmans, Leo Gj; Rodenburg, Richard Jt.
In: Human Mutation, 2017.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive
AU - Baertling, Fabian
AU - Al-Murshedi, Fathiya
AU - Sánchez-Caballero, Laura
AU - Al-Senaidi, Khalfan
AU - Joshi, Niranjan P.
AU - Venselaar, Hanka
AU - van den Brand, Mariël Am
AU - Nijtmans, Leo Gj
AU - Rodenburg, Richard Jt
PY - 2017
Y1 - 2017
N2 - COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.
AB - COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.
KW - Complex IV
KW - COX5A
KW - Cytochrome c oxidase
KW - OXPHOS
KW - Pulmonary arterial hypertension
UR - http://www.scopus.com/inward/record.url?scp=85017353401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017353401&partnerID=8YFLogxK
U2 - 10.1002/humu.23210
DO - 10.1002/humu.23210
M3 - Article
C2 - 28247525
AN - SCOPUS:85017353401
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
ER -