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The construction of a transcriptional map for human chromosome 21 requires the generation of a specific catalogue of genes, together with corresponding mapping information. Towards this goal, we conducted a pilot study on a pool of random chromosome 21 cosmids representing 2 Mb of non-contiguous DNA. Exon-amplification and cDNA selection methods were used in combination to extract the coding content from these cosmids, and to derive expressed sequences libraries. These libraries and the source cosmid library were arrayed at high density for hybridisation screening. A strategy was used which related data obtained by multiple hybridisations of clones originating from one library, screened against the other libraries. In this way, it was possible to integrate the information with the physical map and to compare the gene recovery rate of each technique. cDNAs and exons were grouped into bins delineated by EcoRI cosmid fragments, and a subset of 91 cDNAs and 29 exons have been sequenced. These sequences defined 79 non-overlapping potential coding segments distributed in 24 transcriptional units, which were mapped along 21q. Northern blot analysis performed for a subset of cDNAs indicated the existence of a cognate transcript. Comparison to databases indicated three segments matching to known chromosome 21 genes: PFKL, COL6A1 and S100B and six segments matching to unmapped anonymous expressed sequence tags (ESTs). At the translated nucleotide level, strong homologies to known proteins were found with ATP-binding transporters of the ABC family and the dihydroorotase domain of pyrimidine synthetases. These data strongly suggest that bona fide partial genes have been isolated. Several of the newly isolated transcriptional units map to clinically important regions, in particular those involved in Down's syndrome, progressive myoclonus epilepsia and auto-immune polyglandular disease. The study presented here illustrates the complementarity of exon-amplification and cDNA selection techniques for generating a large resource of new expressed landmarks, which contribute to the construction of a chromosome 21 transcript map.
Hum Mol Genet 1995 Aug
PMID:Model for a transcript map of human chromosome 21: isolation of new coding sequences from exon and enriched cDNA libraries. 758 66

We report on a new maternally-inherited syndrome characterized by a combination of sensorineural hearing loss, ataxia and myoclonus in a large kindred from Sicily. Hearing loss was the most widespread and sometimes the only symptom found in family members. Sequence analysis of the mitochondrial DNA regions encompassing the tRNA genes revealed the presence of a heteroplasmic insertion at nucleotide position 7472. The insertion adds a seventh cytosine to a six-cytosine run that is part of the mitochondrial tRNASer(UCN) gene. Conformational analysis showed that this mutation is likely to alter the structure of the T psi C loop in the tRNASer(UCN) clover leaf secondary structure. Moreover, the degree of heteroplasmy in blood and muscle was correlated with the clinical phenotype, and homoplasmic mutant hybrids showed decreased complex I activity, low oxygen consumption and high lactic acid output, indicating faulty oxidative phosphorylation. Finally, mutation was absent in 381 unrelated maternal lineages, suggesting specific segregation with the disease. We propose that the C7472 insertion-mutation is pathogenic, and etiologically related to hearing loss and other symptoms that define a novel maternally-inherited clinical entity.
Hum Mol Genet 1995 Aug
PMID:Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. 758 83

In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features.
Biochem Mol Biol Int 1994 Aug
PMID:Oxidative stress and mitochondrial dysfunction in neurodegeneration. 784 18

Dentatorubral and pallidoluysian atrophy (DRPLA) belongs to a group of trinucleotide diseases in humans associated with an expanded and unstable (CAG) > 49 repeat within a gene of unknown function. Clinically, DRPLA presents with variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. Hardly anything is known about the physiological function of the DRPLA gene and the pathological mechanisms causing neuronal cell death and leading to these symptoms. To analyze some of these aspects of the DRPLA gene we isolated the complete coding region of the rat DRPLA gene (rdrpla) and investigated its expression in different developmental stages of rodent tissues. The rdrpla gene shows 92% homology in amino acid sequence to the human gene. In rat the length of the (CAG)n repeat is reduced compared to the human (CAG)n block containing 7-34 repeats with an average of 15. Northern blot analysis revealed that in rodents the rdrpla gene is already expressed during embryo development. In addition this transcript is predominantly represented in neuronal tissues throughout all developmental stages investigated.
Hum Mol Genet 1995 Sep
PMID:Predominant neuronal expression of the gene responsible for dentatorubral-pallidoluysian atrophy (DRPLA) in rat. 854 49

Progressive myoclonus epilepsy of the Lafora type (Lafora's disease) is an autosomal recessive disease characterized by epilepsy, myoclonus, dementia, and periodic acid-Schiff-positive intracellular inclusion bodies. The inclusion deposits consist of branched polysaccharides (polyglucosans) but the responsible biochemical defect has not been identified. Onset is during late childhood or adolescence and the disease leads to a fatal outcome within a decade of first symptoms. We studied nine families in which Lafora's disease had been proven by biopsy in at least one member. In order to locate the responsible gene, we screened the human genome with microsatellite markers spaced an average of 13 cM. We used linkage analysis in all nine families and homozygosity mapping in four consanguineous families to define the Lafora's disease gene region. Two point linkage analysis resulted in a total peak lod score of 10.54 for marker D6S311. Six additional chromosome 6q23-25 microsatellites yielded lod scores ranging from 5.92 to 9.60 at theta m = f = 0. An extended pedigree with five affected members independently proved linkage with peak lod scores over 3.8 at theta m = f = 0 for D6S292, D6S403, and D6S311. The multipoint one-lod-unit support interval covered a 2.5 cM region surrounding D6S403. Homozygosity mapping defined a 17 cM region in chromosome 6q23-25 flanked by D6S292 and D6S420 that contains the Lafora's disease gene.
Hum Mol Genet 1995 Sep
PMID:The gene for progressive myoclonus epilepsy of the Lafora type maps to chromosome 6q. 854 57

Nova-1, an autoantigen in paraneoplastic opsoclonus myoclonus ataxia (POMA), a disorder associated with breast cancer and motor dysfunction, is a neuron-specific nuclear RNA binding protein. We have identified in vivo Nova-1 RNA ligands by combining affinity-elution-based RNA selection with protein-RNA immunoprecipitation. Starting with a pool of approximately 10(15) random 52-mer RNAs, we identified long stem-loop RNA ligands that bind to Nova-1 with high affinity (Kd of approximately 2 nM). The loop region of these RNAs harbors a approximately 15-bp pyrimidine-rich element [UCAU(N)(0-2)]3 which is essential for Nova-1 binding. Mutagenesis studies defined the third KH domain of Nova-1 and the [UCAU(N)(0-2)]3 element as necessary for in vitro binding. Consensus [UCAU (N)(0-2)], elements were identified in two neuronal pre-mRNAs, one encoding the inhibitory glycine receptor alpha2 (GlyR alpha2) and a second encoding Nova-1 itself. Nova-1 protein binds these RNAs with high affinity and specificity in vitro, and this binding can be blocked by POMA antisera. Moreover, both Nova-1 and GlyR alpha2 pre-mRNAs specifically coimmunoprecipitated with Nova-1 protein from brain extracts. Thus, Nova-1 functions as a sequence-specific nuclear RNA binding protein in vivo; disruption of the specific interaction between Nova-1 and GlyR alpha2 pre-mRNA may underlie the motor dysfunction seen in POMA.
Mol Cell Biol 1997 Jun
PMID:The neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo. 915 18

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.
Hum Mol Genet 1997 May
PMID:Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. 915 45

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.
Mol Neurobiol 1997 Jun
PMID:Molecular biology of glycinergic neurotransmission. 929 60

MERRF (myoclonic epilepsy with ragged-red fibers) is a severe, multisystem disorder characterized by myoclonus, seizures, progressive cerebellar syndrome, muscle weakness, and the presence of ragged-red fibers in the muscle biopsy. MERRF is associated with heteroplasmic point mutations, either A8344G or T8356C, in the gene encoding the mitochondrial tRNA(Lys). The human rho degree cell system was utilized to examine the phenotypic consequences of these mutations, and to investigate their molecular genetic causes. Wild-type and mutant transmitochondrial cell lines harboring a pathogenic point mutation at either A8344G or T8356C in the human mitochondrial tRNA(Lys) gene were isolated and examined. Mitochondrial transformants containing 100% mutated mitochondrial DNAs (mtDNAs) exhibited severe defects in respiratory chain activity, in the rates of protein synthesis, and in the steady-state levels of mitochondrial translation products as compared with mitochondrial transformants containing 100% wild-type mtDNAs. In addition, both mutant cell lines exhibited the presence of aberrant mitochondrial translation products. These results demonstrate that two different mtDNA point mutations in tRNA(Lys) result in fundamentally identical defects at the cellular level, and that these specific protein synthesis abnormalities contribute to the pathogenesis of MERRF.
Mol Cell Biochem 1997 Sep
PMID:Point mutations in the mitochondrial tRNA(Lys) gene: implications for pathogenesis and mechanism. 930 90

Homozygous leaner mice carry an autosomal recessive mutation in the Ca2+ channel subunit gene, alpha1A, causing them to exhibit severe ataxia, petit-mal-like epilepsy and a myoclonus-like movement disorder. Expression of alpha1A mRNA in cerebella from 20-day-old homozygous leaner mice was compared to control mice, using in situ hybridization histochemistry. Expression of alpha1A protein was examined in cerebella from 20-day-old homozygous leaner and control mice using immunocytochemistry. No differences in either mRNA or protein expression of the alpha1A subunit were observed when homozygous leaner mice were compared to age-matched controls. Therefore, functional alterations in P/Q-Type Ca2+ channels containing the alpha1A subunit need to be explored to further understand the relationship of mutations in the alpha1A gene to the pathogenesis of the neurologic disorders occurring in leaner mice.
Brain Res Mol Brain Res 1998 Aug 15
PMID:Expression of calcium channel alpha1A mRNA and protein in the leaner mouse (tgla/tgla) cerebellum. 972 1


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