Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 May;5(5):e1000487.
doi: 10.1371/journal.pgen.1000487. Epub 2009 May 22.

CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait

Seval Türkmen  1 , Gao Guo, Masoud Garshasbi, Katrin Hoffmann, Amjad J Alshalah, Claudia Mischung, Andreas Kuss, Nicholas Humphrey, Stefan Mundlos, Peter N Robinson
Affiliations

CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait

Seval Türkmen et al. PLoS Genet. 2009 May.

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.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Abbreviated pedigree showing the inferred haplotypes of the parents and the four affected children.
The SNPs A-1511204 and A-1509289 are homozygous in the mother and therefore noninformative for the maternally derived recombination in this region. Therefore, these markers were not fully informative with respect to the critical recombination on the maternally inherited haplotype in affected individual II-1.
Figure 2
Figure 2. CA8 Mutations in two families with ataxia and mild mental retardation.
(A) Affected members of an Iraqi family displayed quadrupedal gait. (B) Sequence traces of the mutation c.298T>C (S100P) in CA8 and a wildtype control (wt). (C) Sequence logo of an alignment of CA8 orthologs from 12 species from human to sea urchin showing the sequence affected by S100P. Position 100 does not show a high degree of conservation.
Figure 3
Figure 3. Blot overlay analysis of CA8-ITPR1 binding.
A recombinant fibrillin-1 fragment rFib47wt was used as negative control (−).
Figure 4
Figure 4. Relative expression levels of Flag-CA8 WT and S100P, tetracycline-inducible Flip-In T-REx-293 cells were grown in the absence or presence of 1 µg/ml tetracycline for 24 hours.
GAPDH was used to normalize the individual expression levels (run in triplicate). There is no significant difference between the mRNA levels of mutant or wildtype CA8. n.s.: Non-significant.
Figure 5
Figure 5. The mutation S100P reduces CA8 protein stability by means of proteasome-mediated CA8 degradation.
(A) Reduction of CA8 protein concentration by S100P. Production of wildtype and mutant CA8 was induced by tetracycline. There was a strong reduction in the level of mutant CA8 protein compared to that of the wildtype at both 0.1, and 1.0 µg/ml tetracycline. *: formula image, **: formula image, comparison between mutant and wildtype at the indicated tetracycline concentration by two-sided t-test. The expression is represented as signal intensity ratio between CA8/GAPDH, which was normalized to the WT level induced by 1 µg/ml tetracycline. Mean values±standard deviation (SD) in triplicate experiments are shown. (B) Rescue of mutant CA8 protein expression by proteasomal inhibition. Addition of the proteasome inhibitor MG132 lead to a dose-dependent rescue of CA8 concentration. *: formula image, comparison between 0 µM MG132 and 0.4 µM or 2.0 µM MG132. Expression is shown as ratio relative to that of the mutant CA8 protein (S100P) without MG132. Mean values±SD in triplicate experiments are shown.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291–304. - PubMed
    1. Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 2007;6:245–257. - PubMed
    1. Boycott KM, Flavelle S, Bureau A, Glass HC, Fujiwara TM, et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet. 2005;77:477–483. - PMC - PubMed
    1. Ozcelik T, Akarsu N, Uz E, Caglayan S, Gulsuner S, et al. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA. 2008;105:4232–4236. - PMC - PubMed
    1. Türkmen S, Hoffmann K, Demirhan O, Aruoba D, Humphrey N, et al. Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene. Eur J Hum Genet. 2008;16:1070–1074. - PubMed

MeSH terms