CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

Abstract

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis 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 mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P 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. CA8 thus 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. Our 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.

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy

“…One Turkish family maps to chromosome 17 [38] and an Iraqi family links to chromosome 8 with a recent study identifying CA8 as the causative gene [39]. Finally, other families exclude linkage to any of these three loci ( [18] and personal communication with Dr. Tayfun Ozcelik).…”

An update on carbonic anhydrase-related proteins VIII, X and XI

“…These studies include determining the role of CARP VIII in development of cancer, the involvement in neurodegeneration both in mouse and human, structural basis of its inactivity, and its role in other pathological conditions 8,9,[14][15][16][17][18] . In our laboratory, we have performed the phylogenetic analysis to study the evolutionary history across the species and detailed expression analysis in several mouse tissues at mRNA and protein level 12 .…”

“…Interestingly, the waddler (wd) mice, which were discovered in 1959 but are now extinct, produced a similar phenotype to the wdl mice 22 . CARP VIII research recently gained a lot of new interest when the first human CA8 gene defect was reported in an Iraqi family 8 . The affected members of the family had mild mental retardation and congenital ataxia accompanied by quadrupedal gait.…”

“…Since then several expression studies have been performed on CARP VIII in both mouse and human [3][4][5][6] . The association of CARP VIII with ataxia and neurodegeneration in humans has been studied recently 7,8 , and the crystal structure of human CARP VIII has been reported [7][8][9] . After the discovery of the first CARP VIII gene in 1990, many more cDNAs have been reported in mice and humans (Table 1) 10 .…”

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

“…Car8 encodes a protein that is designated as carbonic anhydrase VIII, despite its lack of carbonic anhydrase activity. Mice carrying non-functional Car8 mutations suffer from neurological defects [131]. The Asph gene is expressed from two promoters and undergoes extensive alternative splicing, resulting in a set of aspartate beta-hydroxylases that have distinct functional properties.…”