Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incorporation of [1-14C]palmitic or [1-14C]oleic acid into phosphatidylcholine and the effect on blood group antigen expression were examined in human erythrocytes stored at 4 degrees C for 0-3 weeks. Blood drawn into EDTA was obtained by venepuncture from healthy volunteers. A 50% suspension of washed erythrocytes was incubated in buffer containing [1-14C]fatty acid for up to 60 min at 37 degrees C with moderate shaking. Phosphatidylcholine was extracted and analyzed for uptake of radiolabelled fatty acid and phospholipid phosphorus content. Incorporation of [1-14C]palmitic or [1-14C]oleic acid into phosphatidylcholine was reduced during storage. The mechanism for the reduction in radiolabelled fatty acid incorporation into phosphatidylcholine was a 64% (p < 0.05) reduction in membrane phospholipase A2 activity. Although human erythrocyte membranes isolated from freshly drawn blood are capable of reacylating lysophosphatidylcholine to phosphatidylcholine, with storage, a markedly different substrate preference between palmitoyl-Coenzyme A and oleoyl-Coenzyme A was observed. Lysophosphatidylcholine acyltransferase activity assayed with oleoyl-Coenzyme A was unaltered with storage. In contrast, lysophosphatidylcholine acyltransferase activity assayed with palmitoyl-Coenzyme A was elevated 5.5-fold (p < 0.05). Despite these changes, storage of erythrocytes for up to 3 weeks did not result in altered expression of the various blood group antigens investigated. We conclude that the incorporation of palmitate and oleate into phosphatidylcholine is dramatically reduced during storage of human erythrocytes. The observed differential in vitro substrate utilization suggests that distinct acyltransferases are involved in the acylation of lysophosphatidylcholine to phosphatidylcholine in human erythrocytes.
Mol Cell Biochem 2000 Oct
PMID:Incorporation of fatty acids into phosphatidylcholine is reduced during storage of human erythrocytes: evidence for distinct lysophosphatidylcholine acyltransferases. 1112 52

Sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins derived from a common precursor protein (prosaposin) encoded by a single gene. They are required for in vivo degradation of sphingolipids with short carbohydrate chains. Six cysteines and one glycosylation site are strictly conserved in all four saposins. Total deficiency of all saposins and specific deficiency of saposin B or C are known among human patients. A mouse model of total saposin deficiency closely mimics the human disease. However, no specific saposin A or D deficiency is known. We introduced an amino acid substitution (C106F) into the saposin A domain by the Cre/loxP system which eliminated one of the three conserved disulfide bonds. Saposin A(-/-) mice developed slowly progressive hind leg paralysis with clinical onset at approximately 2.5 months and survival up to 5 months. Tremors and shaking, prominent in other myelin mutants, were not obvious until the terminal stage. Pathology and analytical biochemistry were qualitatively identical to, but generally much milder than, that seen in the typical infantile globoid cell leukodystrophy (GLD) in man (Krabbe disease) and in several other mammalian species, due to genetic deficiency of lysosomal galactosylceramidase (GALC) (EC 3.2.1.46). Thus, saposin A is indispensable for in vivo degradation of galactosylceramide by GALC. It should now be recognized that, in addition to GALC deficiency, genetic saposin A deficiency could also cause chronic GLD. Genetic saposin A deficiency might be anticipated among human patients with undiagnosed late-onset chronic leukodystrophy without GALC deficiency.
Hum Mol Genet 2001 May 15
PMID:A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. 1137 12

Among the many phenotypes associated with Gaucher disease, the inherited deficiency of glucocerebrosidase, are reports of patients with parkinsonian symptoms. The basis for this association is unknown, but could be due to alterations in the gene or gene region. The human glucocerebrosidase gene, located on chromosome 1q21, has a nearby pseudogene that shares 96% identity. Immediately adjacent to the glucocerebrosidase pseudogene is a convergently transcribed gene, metaxin, which has a pseudogene that is located just downstream to the glucocerebrosidase gene. We describe a patient with mild Gaucher disease but impaired horizontal saccadic eye movements who developed a tremor at age 42, followed by rapid deterioration of her gait. A pallidotomy at age 47 was unsuccessful. Her motor and cognitive deterioration progressed despite enzyme replacement therapy. Sequencing of the glucocerebrosidase gene identified mutations L444P and D409H. Southern blot analysis using the enzyme SspI showed that the maternal allele had an additional 17-kb band. PCR amplifications and sequencing of this fragment demonstrated a duplication which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion. Gene alterations associated with this novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene, could contribute to the atypical phenotype encountered in this patient.
Mol Genet Metab 2001 Aug
PMID:Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. 1150 13

Scn8a encodes an abundant, widely distributed voltage-gated sodium channel found throughout the central and peripheral nervous systems. Mice with different mutant alleles of Scn8a provide models of the movement disorders ataxia, dystonia, tremor and progressive paralysis. We previously reported that the phenotype of the hypomorphic allele of Scn8a, medJ, is dependent upon an unlinked modifier locus, Scnm1. Strain C57BL/6J carries a sensitive allele of the modifier locus that results in juvenile lethality. We now provide evidence that the modifier acts on the splicing efficiency of the mutant splice donor site. Mutant mice display either 90% or 95% reduction in the proportion of correctly spliced mRNA, depending on modifier genotype. The abundance of the channel protein, Na(v)1.6, is also reduced by an order of magnitude in medJ mice, resulting in delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass and reduction of brain metabolic activity. medJ mice provide a model for the physiological effects of sodium channel deficiency and the molecular mechanism of bigenic disease.
Hum Mol Genet 2002 Oct 15
PMID:Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). 1237 66

Accumulation of reactive oxygen species (ROS), which is generated during energy metabolism, is a cause of physiological aging, neuropathogenesis and numerous diseases, such as Parkinson's and Alzheimer's diseases. Zitter rat is an autosomal recessive mutant, characterized by spongiform degeneration and hypomyelination in the brain, and the phenotype has been suggested to be involved in oxidative stress by the accumulation of ROS. To determine the relation between neurodegeneration of the zitter rat and Attractin (Atrn) gene expression, which was identified as a gene responsible for the zitter, we established fibroblast cells from the zitter rat (Fz) and the Wistar tremor control (WTC) rat (Fw), and transduced Fz cells with the Atrn gene (Fz/Atrn). In the Fz/Atrn cells, accumulation of ROS was repressed, and cell survival against oxidative stress was enhanced to the same level as in Fw cells. Interestingly, phosphorylation of ERK was significantly increased in Fz/Atrn cells by H(2)O(2) stimulus, similarly to Fw cells. Furthermore, activation of ERK was confirmed in the brains of WTC and zitter rats by Western blot analysis and immunohistochemistry. These observations suggested that lack of Atrn gene expression induced neurodegeneration by a decrease in active ERK through an intracellular signaling via oxidative stress.
Brain Res Mol Brain Res 2003 Mar 17
PMID:Pivotal role of attractin in cell survival under oxidative stress in the zitter rat brain with genetic spongiform encephalopathy. 1265 11

Recent studies have reported that alleles in the premutation range in the FMR1 gene in males result in increased FMR1 mRNA levels and at the same time mildly reduced FMR1 protein levels. Some elderly males with premutations exhibit an unique neurodegenerative syndrome characterized by progressive intention tremor and ataxia. We describe neurohistological, biochemical and molecular studies of the brains of mice with an expanded CGG repeat and report elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the proteasome as constituents. An increase was observed of both the number and the size of the inclusions during the course of life, which correlates with the progressive character of the cerebellar tremor/ataxia syndrome in humans. The observations in expanded-repeat mice support a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggest a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. This mouse model will facilitate the possibilities to perform studies at the molecular level from onset of symptoms until the final stage of the disease.
Hum Mol Genet 2003 May 01
PMID:The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. 1270 Jan 64

The FMR1 gene is involved in three different syndromes, the Fragile X syndrome, premature ovarian failure (POF) and the Fragile X-associated tremor/ataxia syndrome (FXTAS) at older age. Fragile X syndrome is caused by an expanded CGG repeat above 200 units in the FMR1 gene resulting in the absence of the FMR1 mRNA and protein. The FMR1 protein is proposed to act as a regulator of mRNA transport and/or translation that plays a role in synaptic maturation and function. POF and FXTAS are found in individuals with an expanded repeat between 50 and 200 CGGs and are associated with increased FMR1 mRNA levels. The presence of elevated FMR1 mRNA in all patients suggests that these syndromes may represent a gain-of-function effect from the elevated message levels. The level of FMR1 mRNA is in fragile balance and is therefore critical for normal functioning.
Hum Mol Genet 2003 Oct 15
PMID:A fragile balance: FMR1 expression levels. 1295 62

The single-stranded DNA- and RNA-binding protein, Puralpha, has been implicated in many biological processes, including control of transcription of multiple genes, initiation of DNA replication, and RNA transport and translation. Deletions of the PURA gene are frequent in acute myeloid leukemia. Mice with targeted disruption of the PURA gene in both alleles appear normal at birth, but at 2 weeks of age, they develop neurological problems manifest by severe tremor and spontaneous seizures and they die by 4 weeks. There are severely lower numbers of neurons in regions of the hippocampus and cerebellum of PURA(-/-) mice versus those of age-matched +/+ littermates, and lamination of these regions is aberrant at time of death. Immunohistochemical analysis of MCM7, a protein marker for DNA replication, reveals a lack of proliferation of precursor cells in these regions in the PURA(-/-) mice. Levels of proliferation were also absent or low in several other tissues of the PURA(-/-) mice, including those of myeloid lineage, whereas those of PURA(+/-) mice were intermediate. Evaluation of brain sections indicates a reduction in myelin and glial fibrillary acidic protein labeling in oligodendrocytes and astrocytes, respectively, indicating pathological development of these cells. At postnatal day 5, a critical time for cerebellar development, Puralpha and Cdk5 were both at peak levels in bodies and dendrites of Purkinje cells of PURA(+/+) mice, but both were absent in dendrites of PURA(-/-) mice. Puralpha and Cdk5 can be coimmunoprecipitated from brain lysates of PURA(+/+) mice. Immunohistochemical studies reveal a dramatic reduction in the level of both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Overall results are consistent with a role for Puralpha in developmentally timed DNA replication in specific cell types and also point to a newly emerging role in compartmentalized RNA transport and translation in neuronal dendrites.
Mol Cell Biol 2003 Oct
PMID:Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. 1297 5

Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Val genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena.
Curr Mol Med 2004 Jun
PMID:Genetic studies in relation to kuru: an overview. 1535 68

The LDL receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor that is highly expressed on neurons. Neuronal LRP1 in vitro can mediate ligand endocytosis, as well as modulate signal transduction processes. However, little is known about its role in the intact nervous system. Here, we report that mice that lack LRP1 selectively in differentiated neurons develop severe behavioral and motor abnormalities, including hyperactivity, tremor, and dystonia. Since their central nervous systems appear histoanatomically normal, we suggest that this phenotype is likely attributable to abnormal neurotransmission. This conclusion is supported by studies of primary cultured neurons that show that LRP1 is present in close proximity to the N-methyl-D-aspartate (NMDA) receptor in dendritic synapses and can be coprecipitated with NMDA receptor subunits and the postsynaptic density protein PSD-95 from neuronal cell lysates. Moreover, treatment with NMDA, but not dopamine, reduces the interaction of LRP1 with PSD-95, indicating that LRP1 participates in transmitter-dependent postsynaptic responses. Together, these findings suggest that LRP1, like other ApoE receptors, can modulate synaptic transmission in the brain.
Mol Cell Biol 2004 Oct
PMID:Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. 1545 62


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