Alternative titles; symbols
HGNC Approved Gene Symbol: COASY
SNOMEDCT: 732264002;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:42,562,148-42,566,277 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Neurodegeneration with brain iron accumulation 6 | 615643 | Autosomal recessive | 3 |
| Pontocerebellar hypoplasia, type 12 | 618266 | Autosomal recessive | 3 |
Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. COASY is a bifunctional enzyme that catalyzes the 2 last steps in CoA synthesis. These activities are performed by 2 separate enzymes, phosphopantetheine adenylyltransferase (PPAT; EC 2.7.7.3) and dephospho-CoA kinase (DPCK; EC 2.7.1.24), in prokaryotes (Daugherty et al., 2002).
By searching for sequences similar to E. coli CoA biosynthesis enzymes, followed by PCR of a brain cDNA library, Daugherty et al. (2002) cloned COASY, which they called PPAT/DPCK. The deduced 565-amino acid protein has an N-terminal domain, a central PPAT domain, and a C-terminal DPCK domain. The PPAT domain contains the conserved HxxH motif characteristic of nucleotidyltransferases. Northern blot analysis detected 2.2- and 2.6-kb COASY transcripts in most tissues and tumor cell lines examined. Expression was highest in kidney and liver and lowest in peripheral blood leukocytes.
By searching for sequences similar to pig Coasy, followed by RT-PCR of a hepatoma cell line cDNA library, Aghajanian and Worrall (2002) cloned human COASY. The deduced protein has a calculated molecular mass of 62.3 kD and shares more than 96% amino acid identity with the pig and mouse proteins. Aghajanian and Worrall (2002) identified a conserved Walker A-type kinase motif, which is involved in ATP binding, in the C-terminal DPCK domain of COASY. Size-exclusion chromatography showed that recombinant human COASY assumed a monomeric native structure with an apparent molecular mass of 62 kD.
Using full-length ribosomal S6 kinase alpha-II (RPS6KA2; 601685) as bait in a yeast 2-hybrid screen of a mouse embryo cDNA library, Zhyvoloup et al. (2002) cloned mouse Coasy, which encodes a deduced 563-amino acid protein. Bioinformatic analysis indicated that the N-terminal extension is only present in eukaryotes.
Nemazanyy et al. (2006) identified and cloned a splicing variant of rat CoA synthase, designating it CoASy-beta and the originally identified variant CoASy-alpha. Bioinformatic analysis suggested the presence of a third splice variant, and the authors designated it CoASy-gamma. CoASy-beta encodes the longest isoform, with a 29-amino acid extension at the N terminus of CoASy-alpha. The N-terminal extension did not affect the activity of CoA synthase but possessed a proline-rich sequence. In contrast to the ubiquitous expression of CoASy-alpha in rats, CoASy-beta was expressed primarily in rat brain. Immunofluorescence assays showed that, like CoASy-alpha, CoASy-beta was also localized to the mitochondria of transfected NIH3T3 cells.
There are 3 splice variants of human COASY: 60-kD COASY-alpha is ubiquitously expressed; COASY-beta has a 29-amino acid extension at the N terminus and is predominantly expressed in the brain; and COASY-gamma is predicted to code for the C-terminal region of CoA synthase corresponding to DPCK (summary by Dusi et al., 2014).
Daugherty et al. (2002) showed that recombinant COASY functioned as the last enzyme within the CoA synthetic pathway, and they verified COASY function by complementation in E. coli. Incubation of PPCS (609853), PPCDC (609854), and COASY with the necessary substrates and cofactors reconstituted the 4-step biochemical transformation of phosphopantothenate to CoA. Mutation analysis confirmed the bifunctional activity of COASY.
Zhyvoloup et al. (2002) confirmed that mouse Coasy is a bifunctional enzyme. Mutation of his203 to ala in the catalytic pocket of the PPAT domain inactivated PPAT activity.
Zhyvoloup et al. (2003) demonstrated that full-length CoA synthase is associated with the outer mitochondrial membrane and that the removal of the N-terminal region relocated the enzyme to the cytosol. The activity of CoA synthase was regulated by phospholipids.
In HeLa cells, Dusi et al. (2014) determined that the COASY protein is mainly present in the mitochondrial matrix, probably anchored to the inner mitochondrial membrane, but that it is also present in cell lysate.
Aghajanian and Worrall (2002) determined that the COASY gene contains 10 exons.
By genomic sequence analysis, Aghajanian and Worrall (2002) mapped the COASY gene to chromosome 17q12-q21.
Neurodegeneration with Brain Iron Accumulation 6
In a 25-year-old woman, born of consanguineous Italian parents, with neurodegeneration with brain iron accumulation-6 (NBIA6; 615643), Dusi et al. (2014) identified a homozygous missense mutation in the COASY gene (R499C; 609855.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Italian patient with a similar disorder was compound heterozygous for R499C and a nonsense mutation (Q59X; 609855.0002). This patient was ascertained from a cohort of 280 NBIA-affected individuals in whom the COASY gene was sequenced. In vitro functional expression assays showed that the R499C mutant protein had lost DPCK enzymatic activity. Fibroblasts of both patients showed decreased levels of acetyl coenzyme A (CoA) and significantly decreased de novo production of CoA and dephospho-CoA, at about 20% of controls, consistent with a loss of function. This was the second inborn error of CoA biosynthesis to be implicated in NBIA, the first being NBIA1 (234200), which is caused by mutation in the PANK2 gene (606157). The phenotype was characterized by progressive motor and cognitive dysfunction beginning in childhood. The patients showed extrapyramidal motor signs, including spasticity, dystonia, and parkinsonism. Brain imaging showed iron accumulation in the basal ganglia.
In 2 sibs, born of unrelated Turkish parents, with NBIA6, Evers et al. (2017) identified compound heterozygous missense mutations in the COASY gene: the previously identified R499C mutation and A214V (609855.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed.
In a patient, born of consanguineous Italian parents, with NBIA6, Annesi et al. (2016) identified homozygosity for the R499C mutation in the COASY gene. The parents were heterozygous for the mutation.
Pontocerebellar Hypoplasia Type 12
In 4 patients from 2 unrelated families with pontocerebellar hypoplasia type 12 (PCH12; 618266), van Dijk et al. (2018) identified homozygous or compound heterozygous loss-of-function mutations in the COASY gene (600855.0004 and 609855.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Analysis of patient cells showed no detectable COASY protein and about 1% enzyme activity. Three of the patients were fetuses, and the one live birth died at 1 month of age, suggesting that complete loss of COASY activity is lethal in humans. Noting that CoA is a fundamental cofactor in multiple metabolic processes, van Dijk et al. (2018) suggested that the affected fetuses survived in utero due to maternal CoA supplementation.
In 2 sibs with PCH12, Rosati et al. (2023) identified a homozygous missense mutation in the COASY gene (R555H; 609855.0006). The mutation, which was identified by whole-genome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In a 25-year-old woman, born of consanguineous Italian parents, with neurodegeneration with brain iron accumulation-6 (NBIA6; 615643), Dusi et al. (2014) identified a homozygous c.1495C-T transition (c.1495C-T, NM_025233.6) in the COASY gene, resulting in an arg499-to-cys (R499C) substitution at a highly conserved residue in the nucleotide-binding site of the DPCK domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in 1 of 13,005 cases in the Exome Variant Server database. Patient fibroblasts showed decreased levels of the mutant protein compared to control, suggesting that the mutant protein is unstable. An unrelated Italian patient with a similar disorder was compound heterozygous for R499C and a c.175C-T transition, resulting in a gln59-to-ter (Q59X; 609855.0002) substitution in the N-terminal regulatory region. Each unaffected parent was heterozygous for 1 of the mutations. This patient was ascertained from a cohort of 280 NBIA-affected individuals in whom the COASY gene was sequenced. Analysis of patient cells indicated that the c.175C-T transcript was subject to mRNA decay. In vitro functional expression assays showed that the R499C mutant protein had lost DPCK enzymatic activity. Fibroblasts of both patients showed decreased levels of acetyl CoA compared to controls, although the difference was statistically significant only for the first patient. Fibroblasts from both patients showed significantly decreased de novo production of CoA and dephospho-CoA, at about 20% of controls. Initially, the mutant R499C protein was able to rescue growth in a yeast-null strain, but the strain became auxotrophic for pantothenate and showed reduced growth, suggesting that the mutant enzyme required a higher concentration of pantothenate to produce enough CoA to sustain growth. The findings indicated that a defect in CoA biosynthesis can cause NBIA.
In 2 sibs, born of unrelated Turkish parents, with NBIA6, Evers et al. (2017) identified compound heterozygous missense mutations in the COASY gene: R499C and A214V (609855.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed.
In a patient, born of consanguineous Italian parents, with NBIA6, Annesi et al. (2016) identified homozygosity for the R499C mutation in the COASY gene. The parents were heterozygous for the mutation.
For discussion of the c.175C-T transition (c.175C-T, NM_025233.6) in the COASY gene, resulting in a gln59-to-ter (Q59X) mutation, that was found in compound heterozygous state in a patient with neurodegeneration with brain iron accumulation-6 (NBIA6; 615643) by Dusi et al. (2014), see 609855.0001.
In 2 sibs, born of unrelated Turkish parents, with neurodegeneration with brain iron accumulation-6 (NBIA6; 615643), Evers et al. (2017) identified compound heterozygous missense mutations in the COASY gene: a c.641C-T transition (c.641C-T, NM_001042532.3), resulting in an ala214-to-val (A214V) substitution at a conserved residue in the PPAT domain, and R499C (609855.0001). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the ExAC database. Functional studies of the variants and studies of patient cells were not performed.
In 3 deceased sibs, born of consanguineous Pakistani parents (family 2), with pontocerebellar hypoplasia type 12 (PCH12; 618266), van Dijk et al. (2018) identified a homozygous C-to-G transversion (c.1486-3C-G, NM_025233.6) in intron 7 of the COASY gene. Analysis of patient cells showed that the mutation resulted in a splicing defect, a frameshift, and premature termination (Ala496IlefsTer20) with no detectable protein expression. Enzymatic activity was reduced to about 1% of control levels. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The first child died at 1 month of age and the other 2 sibs were found to be affected as fetuses; those pregnancies were terminated. A similarly affected fetus from another family (family 1) was compound heterozygous for the c.1486-3C-G mutation and a 2-bp deletion in exon 8 of the COASY gene (c.1549_1550delAG; 609855.0005), resulting in a frameshift and premature termination (Ser517ProfsTer61). Cultured amniocytes from this patient showed no detectable COASY protein and severely reduced enzymatic activity, consistent with a loss of function. Each unaffected parent was heterozygous for 1 of the mutations. The 2-bp deletion was not found in the gnomAD database, whereas the splice site mutation was found at a low frequency in heterozygous state (22 of 277,022 alleles).
For discussion of the 2-bp deletion in exon 8 of the COASY gene (c.1549_1550delAG, NM_025233.6) that was found in compound heterozygous state in a fetus with pontocerebellar hypoplasia type 12 (PCH12; 618266) by van Dijk et al. (2018), see 609855.0004.
In 2 sibs with pontocerebellar hypoplasia type 12 (PCH12; 618266), Rosati et al. (2023) identified homozygosity for a c.1664G-A transition (c.1664G-A, NM_025233.6) in the COASY gene, resulting in an arg555-to-his (R555H) substitution. The mutation, which was identified by whole-genome sequencing, was present in heterozygous state in the parents. The variant was present at a low frequency (0.0007%) in only heterozygous state in the gnomAD database. Functional studies were not performed.
Aghajanian, S., Worrall, D. M. Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). Biochem. J. 365: 13-18, 2002. [PubMed: 11994049] [Full Text: https://doi.org/10.1042/BJ20020569]
Annesi, G., Gagliardi, M., Iannello, G., Quattrone, A., Iannello, G., Quattrone, A. Mutational analysis of COASY in an Italian patient with NBIA. Parkinsonism Relat. Disord. 28: 150-151, 2016. [PubMed: 27021474] [Full Text: https://doi.org/10.1016/j.parkreldis.2016.03.011]
Daugherty, M., Polanuyer, B., Farrell, M., Scholle, M., Lykidis, A., de Crecy-Lagard, V., Osterman, A. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J. Biol. Chem. 277: 21431-21439, 2002. [PubMed: 11923312] [Full Text: https://doi.org/10.1074/jbc.M201708200]
Dusi, S., Valletta, L., Haack, T. B., Tsuchiya, Y., Venco, P., Pasqualato, S., Goffrini, P., Tigano, M., Demchenko, N., Wieland, T., Schwarzmayr, T., Strom, T. M., and 15 others. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 94: 11-22, 2014. [PubMed: 24360804] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.008]
Evers, C., Seitz, A., Assmann, B., Opladen, T., Karch, S., Hinderhofer, K., Granzow, M., Paramasivam, N., Eils, R., Diessl, N., Bartram, C. R., Moog, U. Diagnosis of CoPAN by whole exome sequencing: waking up a sleeping tiger's eye. Am. J. Med. Genet. 173A: 1878-1886, 2017. [PubMed: 28489334] [Full Text: https://doi.org/10.1002/ajmg.a.38252]
Nemazanyy, I., Panasyuk, G., Breus, O., Zhyvoloup, A., Filonenko, V., Gout, I. T. Identification of a novel CoA synthase isoform, which is primarily expressed in the brain. Biochem. Biophys. Res. Commun. 341: 995-1000, 2006. [PubMed: 16460672] [Full Text: https://doi.org/10.1016/j.bbrc.2006.01.051]
Rosati, J., Johnson, J., Stander, Z., White, A., Tortorelli, S., Bailey, D., Fong, C. T., Lee, B. H. Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants. Am. J. Med. Genet. 191A: 842-845, 2023. [PubMed: 36495139] [Full Text: https://doi.org/10.1002/ajmg.a.63076]
van Dijk, T., Ferdinandusse, S., Ruiter, J. P. N., Alders, M., Mathijssen, I. B., Parboosingh, J. S., Innes, A. M., Meijers-Heijboer, H., Poll-The, B. T., Bernier, F. P., Wanders, R. J. A., Lamont, R. E., Baas, F. Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Europ. J. Hum. Genet. 26: 1752-1758, 2018. [PubMed: 30089828] [Full Text: https://doi.org/10.1038/s41431-018-0233-0]
Zhyvoloup, A., Nemazanyy, I., Babich, A., Panasyuk, G., Pobigailo, N., Vudmaska, M., Naidenov, V., Kukharenko, O., Palchevskii, S., Savinska, L., Ovcharenko, G., Verdier, F., Valovka, T., Fenton, T., Rebholz, H., Wang, M.-L., Shepherd, P., Matsuka, G., Filonenko, V., Gout, I. T. Molecular cloning of CoA synthase: the missing link in CoA biosynthesis. J. Biol. Chem. 277: 22107-22110, 2002. [PubMed: 11980892] [Full Text: https://doi.org/10.1074/jbc.C200195200]
Zhyvoloup, A., Nemazanyy, I., Panasyuk, G., Valovka, T., Fenton, T., Rebholz, H., Wang, M.-L., Foxon, R., Lyzogubov, V., Usenko, V., Kyyamova, R., Gorbenko, O., Matsuka, G., Filonenko, V., Gout, I. T. Subcellular localization and regulation of coenzyme A synthase. J. Biol. Chem. 278: 50316-50321, 2003. [PubMed: 14514684] [Full Text: https://doi.org/10.1074/jbc.M307763200]