Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The weaver mutation in mice results in a severe ataxia that is attributable to the degeneration of cerebellar granule cells and dopaminergic neurons in the substantia nigra. Recent genetic studies indicate that the GIRK2 gene is altered in weaver. This gene codes for a G-protein-activated, inwardly rectifying K+ channel protein (8). The mutation results in a single amino acid substitution (glycine-->serine) in the pore-forming H5 region of the channel. The functional consequences of this mutation appear to depend upon the co-expression of other GIRK subunits--leading to either a gain or loss of function. Here, we show that G-protein-activated inwardly rectifying K+ currents are significantly reduced in cerebellar granule cells from animals carrying the mutant allele. The reduction is most pronounced in homozygous neurons. These findings suggest that the death of neurons in weaver is attributable to the loss of GIRK2-mediated currents, not to the expression of a nonspecific cation current.
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PMID:The weaver mutation of GIRK2 results in a loss of inwardly rectifying K+ current in cerebellar granule cells. 885 12

The pleiotropic weaver disease is caused by the mutation of a single amino acid in the G-protein-linked inwardly rectifying K+ channel, GIRK2. In homozygous (wv/wv) animals, the disease is characterized by loss of cerebellar and dopaminergic mesencephalic neurons as well as testicular cells, which produce ataxia, fine tremors, and sterility, respectively. Heterozygous (wv/+) animals show no obvious motor impairments, although some loss of both cerebellar and dopaminergic neurons is observed and wv/+ males become sterile at 3.5 months of age. Abnormal influxes of Na+ and Ca2+ have been linked to cerebellar cell death in wv/wv animals, but it's not clear whether similar changes are observed in wv/+ animals. To discover whether changes in K+-channel function or intracellular Ca2+ concentrations ([Ca2+]i) play a role in the augmented cell loss observed in wv/+ animals when compared with +/+ animals, we studied cultured cerebellar granule cells prepared from either wv/+ or +/+ animals. Resting [Ca2+]i was elevated in wv/+ relative to +/+ animals. Further, depolarizations of cells with elevated K+ solutions elicited much smaller changes in [Ca2+]i in wv/+ animals than in +/+ animals, presumably due to altered GIRK2 channel function. Both wv/+ and +/+ cells showed similar changes in [Ca2+]i when cells were depolarized by glutamate (1 mM), suggesting that both glutamate receptors and Ca2+ channels were unchanged in wv/ + animals. In summary, our results suggest that wv/+ cerebellar granule cells exhibit elevated resting [Ca2+]i levels and altered K+-channel function, which may contribute to the developmental abnormalities and increased cell death observed.
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PMID:Altered responses to potassium in cerebellar neurons from weaver heterozygote mice. 986 Feb 68

In weaver mutant mice, substitution of an amino acid residue in the pore region of GIRK2, a subtype of the G-protein-coupled inwardly rectifying K+ channel, changes the properties of the homomeric channel to produce a lethal depolarized state in cerebellar granule cells and dopaminergic neurons in substantia nigra. Degeneration of these types of neurons causes strong ataxia and Parkinsonian phenomena in the mutant mice, respectively. On the other hand, the mutant gene is also expressed in various other brain regions, in which the mutant may have effects on neuronal survival. Among these regions, we focused on the pontine nuclei, the origin of the pontocerebellar mossy fibres, projecting mainly into the central region of the cerebellar cortex. The results of histological analysis showed that by P9 the number of neurons in the nuclei was reduced in the mutant to about one half and by P18 to one third of those in the wild type, whereas until P7 the number were about the same in wild-type and weaver mutant mice. Three-dimensional reconstruction of the nuclei showed a marked reduction in volume and shape of the mutant nuclei, correlating well with the decrease in neuronal number. In addition, DiI (a lipophilic tracer dye) tracing experiments revealed retraction of pontocerebellar mossy fibres from the cerebellar cortex after P5. From these results, we conclude that projecting neurons in the pontine nuclei, as well as cerebellar granule cells and dopaminergic neurons in substantia nigra, strongly degenerate in weaver mutant mice, resulting in elimination of pontocerebellar mossy fibres during cerebellar development.
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PMID:Degeneration of pontine mossy fibres during cerebellar development in weaver mutant mice. 1227 32

Mice with the weaver mutation exhibit an uneven weave to their gait, ataxia, mild locomotor hyperactivity and, occasionally, tonic-clonic seizures. A single amino acid mutation in a G-protein coupled, inwardly rectifying K+ channel, GIRK2, gives rise to the symptoms seen in the weaver mice. Two areas of the brain are primarily affected. Cerebellar granule cell neurons die soon after birth and dopaminergic neurons are severely depleted in the substantia nigra. In this article we review recent studies of wild-type and mutant GIRK channels found in native cells or introduced into expression systems. We also review two models that explain some of the details leading to the neuronal cell death observed in weaver mice.
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PMID:Cell death in weaver mouse cerebellum. 1287 81

Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K+ channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
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PMID:Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice. 1584 77

Inwardly rectifying potassium (Kir) channels exhibit an asymmetrical conductance at hyperpolarization (high conductance) compared to depolarization (low conductance). The KCNJ10 gene which encodes an inwardly rectifying K+ channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) or SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) syndromes. In this review, we mainly focus on the expression and function of Kir4.1 channels in the inner ear and mutation-induced EAST/SeSAME syndromes to provide insight for understanding the pathogenesis of deafness induced by KCNJ10 deficiency.
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PMID:[EAST/SeSAME syndrome and functional expression of inward rectifier potassium channel Kir4.1 in the inner ear]. 2667 56