Alternative titles; symbols
HGNC Approved Gene Symbol: CA8
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38): 8:60,185,412-60,281,400 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q12.1 | Cerebellar ataxia, impaired intellectual development and dysequilibrium syndrome 3 | 613227 | Autosomal recessive | 3 |
The CA8 (CARP) gene encodes carbonic anhydrase VIII, which is part of a family of zinc metalloenzymes. Although CA8 has a central carbonic anhydrase motif, it lacks carbonic anhydrase activity (EC 4.2.1.1) due to absence of catalytic zinc coordinating residues (Kato, 1990). Nonetheless, the gene product was designated carbonic anhydrase VIII by several workers because it showed a clear sequence identity to other members of the carbonic anhydrase gene family from many sources.
For background information on the CA family, see CA1 (114800).
Kato (1990) discovered a new member of the carbonic anhydrase gene family in a mouse brain cDNA library and demonstrated that it is expressed in the Purkinje cells of the cerebellum. The deduced 291-residue gene product was referred to as CA-related protein, or polypeptide (CARP).
Skaggs et al. (1993) used PCR to amplify the human CARP gene from several cDNA libraries. They found a cDNA with a sequence that was 89.3% identical to mouse CARP at the nucleotide level and 97.9% at the amino acid level.
Bergenhem et al. (1993) found that CARP cosegregated with human chromosome 8. Using human-mouse hybrid mapping and fluorescence in situ hybridization, Bergenhem et al. (1995) demonstrated that the CA8 gene is located on human chromosome 8q11-q12 between the centromere and the CA1/CA2/CA3 cluster at 8q22-q23.
Kelly et al. (1994) mapped the mouse homolog (Car8) to chromosome 4 in a region syntenic to human chromosome 8.
In mouse brain, Hirota et al. (2003) identified Carp as an ITPR1 (147265)-binding protein. Western blot and immunohistochemical studies showed that Carp colocalized and interacted with ITPR1 predominantly in the cytoplasm of cerebellar Purkinje cells. Lower levels of Carp expression were seen in other regions, including cerebrum, olfactory bulb, lung, liver, and adrenal gland. Deletion mutagenesis studies showed that residues 45 to 291 of Carp were essential for its association with the modulatory domain of ITPR1 (residues 1387 to 1647). Carp functioned as an inhibitor of IP3 binding to ITPR1 by reducing the affinity of the receptor for IP3.
By genomewide linkage analysis followed by candidate gene sequencing of a consanguineous Iraqi family with congenital cerebellar ataxia and mild mental retardation (CAMRQ3; 613227), Turkmen et al. (2009) identified a homozygous mutation in the CA8 gene (S100P; 186910.0001) on chromosome 8q12.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the CA8 gene (114815.0002) as the cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2 healthy and 4 affected children.
Kelly et al. (1994) reported absence of CA VIII mRNA in the cerebellum of the 'lurcher' mutant mouse with a neurologic defect.
Sjoblom et al. (1996) constructed a mutant form of mouse Carp by introducing arg117-to-his and glu115-to-gln mutations and showed that this mutated protein binds zinc and catalyzes the hydration of carbon dioxide.
The autosomal recessive 'waddles' (wdl) mouse shows ataxia and appendicular dystonia with frequent tail elevation and an abnormally elevated trunk during ambulation. These changes are readily apparent by 2 weeks of age and persists throughout their life span. The appendicular dystonia produces nearly straight limbs with minimal flexion at the knee and elbow joints, elevation of the pelvis, and a waddling motion during ambulation, particularly at higher velocities. Mutant mice also show increased falling compared to wildtype. These abnormalities occur in the absence of associated pathologic changes in the central or peripheral nervous system. Jiao et al. (2005) determined that the wdl phenotype results from a 19-bp deletion in exon 8 of the Car8 gene on chromosome 4. Mice homozygous for the mutation had almost complete absence of the Car8 protein in Purkinje cells of the cerebellum, consistent with nonsense-mediated decay of mutant transcripts. Itpr1 showed normal expression. The findings indicated that Car8 plays a central role in motor control.
Hirasawa et al. (2007) determined that the autosomal recessive ataxic 'Rigoletto' (rig) mutant mouse has the same 19-bp deletion in Car8 as the wdl mouse. Electrophysiologic studies of cerebellar Purkinje cells from mutant mice showed decreased spontaneous excitatory transmission compared to wildtype mice. Paired pulse ratios were similar in both strains, suggesting that synapses are functional with normal release probability, but that mutants may have a lower number of functional synapses. Light microscopy showed an abnormal extension of climbing fibers to distal Purkinje cell dendrites. Ultrastructural studies showed abnormalities of parallel fibers and dendritic spines, including free spines that did not form normal synapses and multiple synaptic varicosities. Hirasawa et al. (2007) concluded that Car8 plays a critical role in synaptogenesis and/or maintenance of proper synaptic morphology and function in the cerebellum.
In 4 affected sibs of a consanguineous Iraqi family with congenital cerebellar ataxia and mild mental retardation (CAMRQ3; 613227), Turkmen et al. (2009) identified a homozygous 298T-C transition in the CA8 gene, resulting in a ser100-to-pro (S100P) substitution. The mutation was not found in 200 matched controls. All affected individuals showed quadrupedal locomotion. Although there was no apparent difference between the CA8 S100P mutant and wildtype in binding to ITRP1 (147265), in vitro functional expression studies showed that the S100P mutation resulted in decreased protein stability, suggesting a loss of function.
In a family (M107) in which 4 of 6 children of first-cousin parents had moderate intellectual disability and ataxia (CAMRQ3; 613227), Najmabadi et al. (2011) identified a C-to-T transition at genomic coordinate chr8:61297790 (NCBI36) in the CA8 gene, resulting in an arg237-to-gln (R237Q). The mutation was found in homozygosity among affected individuals and segregated with the disease in the family.
Bergenhem, N. C. H., Eddy, R. L., Shows, T. B., Tashian, R. E. Assignment of the gene for human carbonic anhydrase-related protein to chromosome 8. (Abstract) Human Genome Meeting, Kobe, Japan, November 1993.
Bergenhem, N. C. H., Sait, S. S. J., Eddy, R. L., Shows, T. B., Tashian, R. E. Assignment of the gene for human carbonic anhydrase VIII (CA8) to chromosome 8q11-q12. Cytogenet. Cell Genet. 71: 299-300, 1995. [PubMed: 7587398] [Full Text: https://doi.org/10.1159/000134131]
Hirasawa, M., Xu, X., Trask, R.B., Maddatu, T. P., Johnson, B.A., Naggert, J. K., Nishina, P. M., Ikeda, A. Carbonic anhydrase related protein 8 mutation results in aberrant synaptic morphology and excitatory synaptic function in the cerebellum. Molec. Cell. Neurosci. 35: 161-170, 2007. [PubMed: 17376701] [Full Text: https://doi.org/10.1016/j.mcn.2007.02.013]
Hirota, J., Ando, H., Hamada, K., Mikoshiba, K. Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem. J. 372: 435-441, 2003. [PubMed: 12611586] [Full Text: https://doi.org/10.1042/BJ20030110]
Jiao, Y., Yan, J., Zhao, Y., Donahue, L. R., Beamer, W. G., Li, X., Roe, B. A., LeDoux, M. S., Gu, W. Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics 171: 1239-1246, 2005. [PubMed: 16118194] [Full Text: https://doi.org/10.1534/genetics.105.044487]
Kato, K. Sequence of a novel carbonic anhydrase-related polypeptide and its exclusive presence in Purkinje cells. FEBS Lett. 271: 137-140, 1990. [PubMed: 2121526] [Full Text: https://doi.org/10.1016/0014-5793(90)80390-5]
Kelly, C., Nogradi, A., Walker, R., Caddy, K., Peters, J., Carter, N. Lurching, reeling, waddling and staggering in mice: is carbonic anhydrase (CA) VIII a candidate gene? Biochem. Soc. Trans. 22: 359S, 1994. [PubMed: 7821612] [Full Text: https://doi.org/10.1042/bst022359s]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Sjoblom, B., Elleby, B., Wallgren, K., Jonsson, B.-H., Lindskog, S. Two point mutations convert a catalytically inactive carbonic anhydrase-related protein (CARP) to an active enzyme. FEBS Lett. 398: 322-325, 1996. [PubMed: 8977131] [Full Text: https://doi.org/10.1016/s0014-5793(96)01263-x]
Skaggs, L. A., Bergenhem, N. C. H., Venta, P. J., Tashian, R. E. The deduced amino acid sequence of human carbonic anhydrase-related protein (CARP) is 98% identical to the mouse homologue. Gene 126: 291-292, 1993. [PubMed: 8482548] [Full Text: https://doi.org/10.1016/0378-1119(93)90385-g]
Turkmen, S., Guo, G., Garshasbi, M., Hoffmann, K., Alshalah, A.J., Mischung, C., Kuss, A., Humphrey, N., Mundlos, S., Robinson, P. N. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet. 5: e1000487, 2009. Note: Electronic Article. [PubMed: 19461874] [Full Text: https://doi.org/10.1371/journal.pgen.1000487]