A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease.
Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) 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(10) 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(10) 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(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth.
Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
Andrew J
AJ
Duncan
Maria
M
Bitner-Glindzicz
Brigitte
B
Meunier
Harry
H
Costello
Iain P
IP
Hargreaves
Luis C
LC
López
Michio
M
Hirano
Catarina M
CM
Quinzii
Michael I
MI
Sadowski
John
J
Hardy
Andrew
A
Singleton
Peter T
PT
Clayton
Shamima
S
Rahman
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D018389:Codon, Nonsense; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology; D014451:Ubiquinone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D018389:Codon, Nonsense; D029701:Saccharomyces cerevisiae Proteins; D014451:Ubiquinone; C030571:ubiquinone 9