The CA8 gene encodes carbonic anhydrase VIII (CARP VIII), which is part of a family of zinc metalloenzymes that catalyze the reversible hydration of bicarbonate. Although CA8 has a central carbonic anhydrase motif, it lacks classical carbonic anhydrase activity (i.e., the reversible hydration of carbon dioxide) due to the absence of one or more histidine residues required for binding to the zinc ion, which is critical for CO2 hydration activity. Nonetheless, the gene product continues to carry a carbonic anhydrase designation because it showed a clear sequence identity to other members of the carbonic anhydrase gene family. The absence of CA8 gene transcription in the cerebellum of the “lurcher” mutant in mice with a neurologic defect suggests an important role for this acatalytic form. The sole known biochemical function of CA8 is to inhibit inositol 1,4,5-triphosphate (IP3) binding to IP3 receptor 1 (ITPR1). However, the exact biological function of CA8 is still unknown.
The CA8 gene is located on the long arm of chromosome 8 at 8q11-q12 and it consists of eight coding exons. The CARP VIII protein includes 290 amino acids and weights 32.9 kDa. It is mainly expressed in Purkinje cells of the cerebellum and in a wide variety of other tissues both in mouse and human. This protein has been linked to development of colorectal and lung cancers in humans, and the overexpression of it has been observed in several other cancers.
Mutations in the CA8 gene are responsible for cerebellar ataxia mental retardation and dysequilibrium syndrome type 3 (CMARQ3). CMARQ3 is a congenital cerebellar ataxia associated with dysarthia, quadrupedal gait, and mild mental retardation.
Turkmen et al. (2009) performed a genome-wide linkage analysis of a consanguineous Iraqi family with four affected sibs with mild mental retardation and congenital ataxia characterized by quadrupedal gait [congenital cerebellar ataxia and mild mental retardation (CAMRQ3)]. They identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous transition c.298T>C, predicted to lead to the substitution of a serine by a proline residue (p.S100P), in all affected individuals. This mutation (c.298T>C) was found to segregate correctly with the disease in the family and was not found in 200 population matched controls. Also, Turkmen et al. (2009) demonstrated that the p.S100P mutation is associated with proteasome-mediated degradation, and, thus, presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. Thus, Turkmen et al. (2009) considered the CA8 represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Turkmen et al. (2009) concluded that these findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.
Kaya et al. (2011) described seven patients with cerebellar ataxia, mental retardation (MR), and disequilibrium syndrome type 3 from three related families. The first family had only one affected member (proband), the second family had four affected members (3 males and one female), and the third family had two affected members (one male and one female). The parents of the first and second families were siblings, and the third family was closely related. The proband was a 9-year-old boy born to consanguineous Saudi parents. Linkage analysis showed a peak on chromosome 8q12.1–8q13.3, with a LOD score of 5.1, that harbors the CA8 gene in which a novel homozygous c.484G>A (p.G162R) mutation in exon 4 was identified in all seven patients. The parents of the three families were heterozygous for the same mutation. This mutation was not found in 200 unrelated healthy Saudi controls.
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