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COENZYME 9; COQ9

COENZYME 9; COQ9

Alternative titles; symbolsCOQ9, S. CEREVISIAE, HOMOLOG OFCHROMOSOME 16 OPEN READING FRAME 49; C16ORF49HGNC Approved Gene Symbol: COQ9Cytogenetic location: 16q21...

Alternative titles; symbols

  • COQ9, S. CEREVISIAE, HOMOLOG OF
  • CHROMOSOME 16 OPEN READING FRAME 49; C16ORF49

HGNC Approved Gene Symbol: COQ9

Cytogenetic location: 16q21 Genomic coordinates (GRCh38): 16:57,447,478-57,461,269 (from NCBI)

▼ Description
Coenzyme Q10 (CoQ10), or ubiquinone, is a mobile lipophilic electron carrier critical for electron transfer by the mitochondrial inner membrane respiratory chain. COQ9 is 1 of several enzymes involved in biosynthesis of CoQ10 and likely functions in modification of the benzoquinone ring (Duncan et al., 2009).

▼ Cloning and Expression
Using RT-PCR, Duncan et al. (2009) cloned COQ9 from normal human fibroblast RNA. The deduced 318-amino acid protein is highly conserved in several mammalian species and in chicken and zebrafish.

▼ Gene Function
Johnson et al. (2005) reported that Coq9 was required for biosynthesis of coenzyme Q in S. cerevisiae.

▼ Mapping
By genomic sequence analysis, Loftus et al. (1999) mapped the COQ9 gene to chromosome 16. Duncan et al. (2009) stated that the COQ9 gene maps to chromosome 16q13.

▼ Molecular Genetics
In a Pakistani infant with severe fatal CoQ10 deficiency-5 (COQ10D5; 614654), Duncan et al. (2009) identified a homozygous nonsense mutation in the COQ9 gene (R244X; 612837.0001). The rate of biosynthesis of CoQ10 was only 11% of mean control activity in fibroblasts from the patient.

In a male infant, born of consanguineous Turkish parents, with fatal COQ10D5, Danhauser et al. (2016) identified a homozygous splice site mutation in the COQ9 gene (612837.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies in patient fibroblasts showed absence of COQ9 and a severe decrease in COQ7 (601683) expression and CoQ10 levels. There was also abnormal accumulation of the intermediate 6-demethoxyubiquinone-10, which is the substrate of COQ7.

▼ Animal Model
Garcia-Corzo et al. (2013) found that transgenic mice with a homozygous truncating R239X mutation in the Coq9 gene, which is homologous to the human R244X mutation, developed a severe encephalomyopathy with poor overall growth, impaired motor function, and progressive paralysis resulting in early death between 3 and 6 months of age. Neuropathologic examination showed neuronal death, demyelination, vacuolization, spongiform degeneration, and astrogliosis. The heart showed signs of fibrosis. The brain showed the largest impairment of mitochondrial respiratory function, with loss of ATP and respiratory complex I activity resulting in energy depletion and caspase-independent apoptosis. Mutant mice had a severe reduction of CoQ10, Coq7, and accumulation of demethoxyubiquinone-9, which is the substrate of Coq7.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 COENZYME Q10 DEFICIENCY, PRIMARY, 5
COQ9, ARG244TER
In a child of Pakistani origin with coenzyme Q10 deficiency-5 (COQ10D5; 614654), Duncan et al. (2009) identified homozygosity for a 730C-T transition in exon 7 of the COQ9 gene, resulting in an arg244-to-ter (R244X) mutation that truncated the terminal 75 amino acids of the protein. The mutation was absent in 308 control alleles, including 114 Pakistani controls. Arg244 of the protein is highly conserved through evolution. Site-directed mutagenesis targeting the equivalent residue in S. cerevisiae abolished respiratory growth.

Quinzii et al. (2010) studied fibroblasts carrying the homozygous R244X mutation. CoQ10 levels were decreased to 18% of normal values, and cells showed impaired cell growth in galactose medium after 72 hours as well as decreased ATP levels, but no increase in reactive oxygen species or oxidative stress-induced death. Quinzii et al. (2010) concluded that the pathology caused by this mutation was related to the marked bioenergetic defect, but not to oxidative stress. The authors suggested that absence of mitochondrial respiratory activity may even confer some resistance to stress-induced apoptosis.

.0002 COENZYME Q10 DEFICIENCY, PRIMARY, 5
COQ9, 1-BP DEL, IVS4DS, +1
In a male infant, born of consanguineous Turkish parents, with coenzyme Q10 deficiency-5 (COQ10D5; 614654), Danhauser et al. (2016) identified a homozygous 1-bp deletion (c.521+1del, NM_020312.2) in intron 4 of the COQ9 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 4,500 in-house control exomes; it was listed only once in the heterozygous state in the ExAC database. Analysis of patient fibroblasts showed that the mutation resulted in the skipping of exons 4 and 5 and the deletion of 76 amino acids (Ser127_Arg202del), including essential parts of the lipid-binding cavity. COQ9 was undetectable in patient cells by immunostaining, indicating degradation of the truncated protein; COQ7 (601683) and CoQ10 levels were also decreased in patient cells. Expression of wildtype COQ9 in patient cells rescued the reduced activity of mitochondrial complex II/III and restored CoQ10 and COQ7 levels. In addition, treatment of patient cells with CoQ10 rescued complex II/III activity, suggesting a possible treatment strategy.

Tags: 16q21