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

@article{citeulike:4680405, 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.}, author = {T\"{u}rkmen, Seval and Guo, Gao and Garshasbi, Masoud and Hoffmann, Katrin and Alshalah, Amjad J. and Mischung, Claudia and Kuss, Andreas and Humphrey, Nicholas and Mundlos, Stefan and Robinson, Peter N.}, citeulike-article-id = {4680405}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pgen.1000487}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19461874}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19461874}, day = {22}, doi = {10.1371/journal.pgen.1000487}, issn = {1553-7404}, journal = {PLoS Genet}, keywords = {mental\_retardation, sequence\_logo}, month = {May}, number = {5}, pages = {e1000487+}, posted-at = {2009-11-13 15:23:22}, priority = {2}, publisher = {Public Library of Science}, title = {CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait}, url = {http://dx.doi.org/10.1371/journal.pgen.1000487}, volume = {5}, year = {2009} }

TY - JOUR ID - citeulike:4680405 L3 - citeulike-article-id:4680405 N2 - 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. IS - 5 JF - PLoS Genet SN - 1553-7404 TI - CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait PB - Public Library of Science VL - 5 SP - e1000487 KW - mental_retardation KW - sequence_logo AU - Türkmen, Seval AU - Guo, Gao AU - Garshasbi, Masoud AU - Hoffmann, Katrin AU - Alshalah, Amjad AU - Mischung, Claudia AU - Kuss, Andreas AU - Humphrey, Nicholas AU - Mundlos, Stefan AU - Robinson, Peter PY - 2009/05/22/ UR - http://dx.doi.org/10.1371/journal.pgen.1000487 ER -