A Nonsense Mutation in COQ9 Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency: A Potentially Treatable Form of Mitochondrial Disease
Identifieur interne : 000995 ( Ncbi/Checkpoint ); précédent : 000994; suivant : 000996A Nonsense Mutation in COQ9 Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency: A Potentially Treatable Form of Mitochondrial Disease
Auteurs : Andrew J. Duncan ; Maria Bitner-Glindzicz ; Brigitte Meunier ; Harry Costello ; Iain P. Hargreaves ; Luis C. L Pez ; Michio Hirano ; Catarina M. Quinzii ; Michael I. Sadowski ; John Hardy ; Andrew Singleton ; Peter T. Clayton ; Shamima RahmanSource :
- American Journal of Human Genetics [ 0002-9297 ] ; 2009.
Abstract
Coenzyme Q10 is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q10 biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q10 deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q10 biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q10 deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q10 biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of
Url:
DOI: 10.1016/j.ajhg.2009.03.018
PubMed: 19375058
PubMed Central: 2681001
Affiliations:
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Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q<sub>10</sub>
Deficiency: A Potentially Treatable Form of Mitochondrial Disease</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Nonsense Mutation in <italic>COQ9</italic>
Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q<sub>10</sub>
Deficiency: A Potentially Treatable Form of Mitochondrial Disease</title>
<author><name sortKey="Duncan, Andrew J" sort="Duncan, Andrew J" uniqKey="Duncan A" first="Andrew J." last="Duncan">Andrew J. Duncan</name>
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<series><title level="j">American Journal of Human Genetics</title>
<idno type="ISSN">0002-9297</idno>
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<front><div type="abstract" xml:lang="en"><p>Coenzyme Q<sub>10</sub>
is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q<sub>10</sub>
biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q<sub>10</sub>
deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q<sub>10</sub>
biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q<sub>10</sub>
deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q<sub>10</sub>
biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of <italic>COQ9</italic>
, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast <italic>Saccharomyces cerevisiae</italic>
abolished respiratory growth.</p>
</div>
</front>
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<affiliations><list></list>
<tree><noCountry><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name>
<name sortKey="Clayton, Peter T" sort="Clayton, Peter T" uniqKey="Clayton P" first="Peter T." last="Clayton">Peter T. Clayton</name>
<name sortKey="Costello, Harry" sort="Costello, Harry" uniqKey="Costello H" first="Harry" last="Costello">Harry Costello</name>
<name sortKey="Duncan, Andrew J" sort="Duncan, Andrew J" uniqKey="Duncan A" first="Andrew J." last="Duncan">Andrew J. Duncan</name>
<name sortKey="Hardy, John" sort="Hardy, John" uniqKey="Hardy J" first="John" last="Hardy">John Hardy</name>
<name sortKey="Hargreaves, Iain P" sort="Hargreaves, Iain P" uniqKey="Hargreaves I" first="Iain P." last="Hargreaves">Iain P. Hargreaves</name>
<name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name>
<name sortKey="L Pez, Luis C" sort="L Pez, Luis C" uniqKey="L Pez L" first="Luis C." last="L Pez">Luis C. L Pez</name>
<name sortKey="Meunier, Brigitte" sort="Meunier, Brigitte" uniqKey="Meunier B" first="Brigitte" last="Meunier">Brigitte Meunier</name>
<name sortKey="Quinzii, Catarina M" sort="Quinzii, Catarina M" uniqKey="Quinzii C" first="Catarina M." last="Quinzii">Catarina M. Quinzii</name>
<name sortKey="Rahman, Shamima" sort="Rahman, Shamima" uniqKey="Rahman S" first="Shamima" last="Rahman">Shamima Rahman</name>
<name sortKey="Sadowski, Michael I" sort="Sadowski, Michael I" uniqKey="Sadowski M" first="Michael I." last="Sadowski">Michael I. Sadowski</name>
<name sortKey="Singleton, Andrew" sort="Singleton, Andrew" uniqKey="Singleton A" first="Andrew" last="Singleton">Andrew Singleton</name>
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