Alternative titles; symbols
HGNC Approved Gene Symbol: CA5A
Cytogenetic location: 16q24.2 Genomic coordinates (GRCh38): 16:87,881,549-87,936,529 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.2 | Hyperammonemia due to carbonic anhydrase VA deficiency | 615751 | Autosomal recessive | 3 |
The CA5A gene encodes an intramitochondrial carbonic anhydrase, which is pivotal for providing bicarbonate (HCO3-) for multiple mitochondrial enzymes (summary by van Karnebeek et al., 2014).
Carbonic anhydrases (CAs) are a family of zinc metalloenzymes. For background information on the CA family, see 114800.
Using a mouse cDNA that presumably encoded a mitochondrial carbonic anhydrase, Nagao et al. (1993) isolated a full-length cDNA clone encoding human CA V from a human liver cDNA library. The N-terminal sequence was determined directly on the 30-kD soluble CA V purified from COS cells transfected with the cDNA. These sequence data indicated that processing of the precursor polypeptide to mature human CA V involves removal of a 38-amino acid mitochondrial leader sequence. Nagao et al. (1993) found that the 267-amino acid sequence deduced for mature human CA V is 30 to 49% homologous to amino acid sequences of previously characterized human CAs and 76% homologous to the amino acid sequence deduced from the mouse cDNA for CA5.
By RT-PCR analysis, Fujikawa-Adachi et al. (1999) detected CA5 in liver only, whereas they detected CA5B (300230), another mitochondrial carbonic anhydrase, in pancreas, kidney, salivary glands, and spinal cord, but not in liver.
Nagao et al. (1994) demonstrated that the homologous mouse and rat cDNAs both expressed the CA activity in transfected COS cells. They identified the N-terminal processing sites that are cleaved to produce the mature 31- and 30-kD forms found in mouse and rat liver. Heck et al. (1994) characterized the kinetic properties of the enzyme expressed in bacteria from murine cDNA.
Nagao et al. (1995) showed that the human CA5 gene contains 7 exons in approximately 50 kb of genomic DNA. The exon/intron boundaries are at positions identical to those of other known CA genes.
By PCR analysis of DNAs from human/rodent somatic cell hybrids, Nagao et al. (1993) localized the CA5 gene to human chromosome 16, the same chromosome to which CA7 had been mapped. By FISH, Nagao et al. (1995) mapped the CA5 gene to 16q24.3. They also noted an unprocessed pseudogene containing exons 3-7 and mapped it to 16p12-p11.2.
Lakkis et al. (1997) demonstrated that the mouse homolog, symbolized Car5, maps to chromosome 8.
In 4 patients from 3 unrelated families with early-onset hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD; 615751), van Karnebeek et al. (2014) identified 3 different homozygous mutations in the CA5A gene (114761.0001-114761.0003), resulting in a loss of enzyme function. The mutation in the first family was found by whole-exome sequencing. The disorder was characterized clinically by acute onset of encephalopathy in infancy or early childhood. Biochemical evaluation showed multiple metabolic abnormalities, including metabolic acidosis and respiratory alkalosis. Other abnormalities included hypoglycemia, increased serum lactate and alanine, and evidence of impaired provision of bicarbonate to essential mitochondrial enzymes. Apart from episodic acute events in early childhood, the disorder showed a relatively benign course.
In a cohort of 96 patients with early-onset hyperammonemia, Diez-Fernandez et al. (2016) identified 10 patients with biallelic variants in the CA5A gene. Two unrelated patients carried a glu241-to-lys mutation (E241K; 114761.0004).
In 2 sibs of Belgian Scottish descent with hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD; 615751), van Karnebeek et al. (2014) identified a homozygous c.697T-C transition in the CA5A gene, resulting in a ser233-to-pro (S233P) substitution at a highly conserved residue near the substrate-binding region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137) or Exome Sequencing Project databases, or in 100 in-house exomes or 10 in-house genomes. In vitro functional expression studies in COS-7 cells showed reduced levels of the mutant protein and about 20% residual activity compared to wildtype. The mutant protein also showed temperature sensitivity, losing almost all its activity at 40 degrees C. The findings were consistent with a loss of enzyme function.
In a boy, born of unrelated Russian parents, with carbonic anhydrase VA deficiency (CA5AD; 615751), van Karnebeek et al. (2014) identified a synonymous c.555G-A transition in the last base of exon 4 of the CA5A gene, resulting in a splice site alteration and an in-frame deletion of exon 4. The deleted transcript contains 3 critical residues and is predicted to result in significantly impaired enzyme activity or protein misfolding and degradation.
In a boy, born of consanguineous Pakistani parents (family 3), with carbonic anhydrase VA deficiency (CA5AD; 615751), van Karnebeek et al. (2014) identified a homozygous 4-kb deletion in the CA5A gene, resulting in the deletion of exon 6. Liver biopsy from the patient showed absence of the CA5A protein. The unaffected parents were heterozygous for the deletion. The homozygous deletion was also found in the patient's older brother who, at age 17 years, reportedly had no major health problems and declined further evaluation. Van Karnebeek et al. (2014) noted the benign clinical course after early childhood in the proband and suggested that the older brother had milder manifestations in childhood or that the condition showed intrafamilial variability, as has been observed in other inborn errors of metabolism.
Diez-Fernandez et al. (2016) identified 5 additional individuals (patients 10-14) with an in-frame deletion of exon 6 (c.619-3420_c.774+502del4078bp, NM_001739.1). Four patients were from Pakistani families, one of which was nonconsanguineous; 1 patient was from a consanguineous Indian Hindu family.
In 2 newborns (patients 7 and 8) with carbonic anhydrase VA deficiency (CA5AD; 615751) who presented with hyperammonemic crisis at 5 and 4 days of age, respectively, Diez-Fernandez et al. (2016) reported a G-to-A transition at nucleotide 721 (c.721G-A, NM_001739.1) in exon 6 of the CA5A gene, resulting in a glutamic acid-to-lysine substitution at codon 241 (E241K). Patient 7 was from a consanguineous Bangladeshi family, and patient 8 was from a Pakistani family whose consanguinity was unknown.
Diez-Fernandez, C., Rufenacht, V., Santra, S., Lund, A. M., Santer, R., Lindner, M., Tangeraas, T., Unsinn, C., de Lonlay, P., Burlina, A., van Karnebeek, C. D. M., Haberle, J. Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis. Genet. Med. 18: 991-1000, 2016. Note: Erratum: Genet. Med. 18: 649 only, 2016. [PubMed: 26913920] [Full Text: https://doi.org/10.1038/gim.2015.201]
Fujikawa-Adachi, K., Nishimori, I., Taguchi, T., Onishi, S. Human mitochondrial carbonic anhydrase VB: cDNA cloning, mRNA expression, subcellular localization, and mapping to chromosome X. J. Biol. Chem. 274: 21228-21233, 1999. [PubMed: 10409679] [Full Text: https://doi.org/10.1074/jbc.274.30.21228]
Heck, R. W., Tanhauser, S. M., Manda, R., Tu, C., Laipis, P. J., Silverman, D. N. Catalytic properties of mouse carbonic anhydrase V. J. Biol. Chem. 269: 24742-24746, 1994. [PubMed: 7929150]
Lakkis, M. M., Venta, P. J., Tashian, R. E. Localization of the mitochondrial carbonic anhydrase V gene, Car5, on mouse chromosome 8. Mammalian Genome 8: 225-226, 1997. [PubMed: 9069129] [Full Text: https://doi.org/10.1007/s003359900396]
Nagao, Y., Batanian, J. R., Clemente, M. F., Sly, W. S. Genomic organization of the human gene (CA5) and pseudogene for mitochondrial carbonic anhydrase V and their localization to chromosomes 16q and 16p. Genomics 28: 477-484, 1995. [PubMed: 7490083] [Full Text: https://doi.org/10.1006/geno.1995.1177]
Nagao, Y., Platero, J. S., Waheed, A., Sly, W. S. Human mitochondrial carbonic anhydrase: cDNA cloning, expression, subcellular localization, and mapping to chromosome 16. Proc. Nat. Acad. Sci. 90: 7623-7627, 1993. [PubMed: 8356065] [Full Text: https://doi.org/10.1073/pnas.90.16.7623]
Nagao, Y., Srinivasan, M., Platero, J. S., Svendrowski, M., Waheed, A., Sly, W. S. Mitochondrial carbonic anhydrase (isozyme V) in mouse and rat: cDNA cloning, expression, subcellular localization, processing, and tissue distribution. Proc. Nat. Acad. Sci. 91: 10330-10334, 1994. [PubMed: 7937950] [Full Text: https://doi.org/10.1073/pnas.91.22.10330]
van Karnebeek, C. D., Sly, W. S., Ross, C. J., Salvarinova, R., Yaplito-Lee, J., Santra, S., Shyr, C., Horvath, G. A., Eydoux, P., Lehman, A. M., Bernard, V., Newlove, T., and 14 others. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am. J. Hum. Genet. 94: 453-461, 2014. [PubMed: 24530203] [Full Text: https://doi.org/10.1016/j.ajhg.2014.01.006]