Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The waddles (wdl) mouse is a unique animal model that exhibits ataxia and appendicular dystonia without pathological abnormalities of either the central or the peripheral nervous systems. A 19-bp deletion in exon 8 of the carbonic anhydrase-related protein VIII gene (Car8) was detected by high-throughput temperature-gradient capillary electrophoresis heteroduplex analysis of PCR amplicons of genes and ESTs within the wdl locus on mouse chromosome 4. Although regarded as a member of the carbonic anhydrase gene family, the encoded protein (CAR8) has no reported enzymatic activity. In normal mice, CAR8 is abundantly expressed in cerebellar Purkinje cells as well as in several other cell groups. Compatible with nonsense-mediated decay of mutant transcripts, CAR8 is virtually absent in mice homozygous for the wdl mutation. These data indicate that the wdl mouse is a Car8 null mutant and that CAR8 plays a central role in motor control.
 ...
PMID:Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. 1611 94

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.
 ...
PMID:CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. 1946 74