Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dystonia musculorum (dt) is an inherited neurodegenerative disorder in mice. The dt gene product, dystonin, contains the bullous pemphigoid antigen 1 coding region at its C-terminus and an actin binding domain at its N-terminus. We demonstrate that dystonin expression throughout mouse development predominates in neurons of the cranial and spinal sensory ganglia. These structures are the most severely affected in dystonic mice which could explain their severe sensory ataxia. Since we show expression in sensory neurons with small and large axoplasmic volumes, but degeneration is restricted primarily to the latter type, we suggest that caliber and size of the axon is an important factor in the disease process. Dystonin is also expressed in the extrapyramidal motor system and in the cerebellum. Functional defects in these cell types could account for the dystonic symptoms of dt mice not explained by simple sensory denervation. We also detect dystonin expression in motor neurons most of which are unaffected by the degenerative process in dt mice.
Mol Cell Neurosci 1995 Dec
PMID:Dystonin expression in the developing nervous system predominates in the neurons that degenerate in dystonia musculorum mutant mice. 874 68

Some cases of spongiform encephalopathies are linked to mutations within the prion protein gene (PRNP). Repetitive octapeptide insertions of variable length in the PRNP gene are also associated with spongiform encephalopathies, mostly familial Creutzfeldt-Jakob disease (CJD). In this study we report on a novel insertion mutation comprising nine extra octapeptide repeats between codons 51 and 91 of the PRNP gene. The affected patient showed a slowly progressive dementia of at least 6 years duration and ataxia.
Brain Res Mol Brain Res 1995 Dec 01
PMID:Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene. 875 Aug 75

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.
Hum Mol Genet 1996 Jan
PMID:Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. 878 34

Ataxia telangiectasia is a recessive disorder in which patients show a progressive cerebellar degeneration leading to ataxia, abnormal eye movements and deterioration of speech. Other features include ocular telangiectasia, high serum AFP levels, immunodeficiency, growth retardation and an increased predisposition to some tumours, particularly T cell leukaemia and lymphoma. We report the 1348 amino acid sequence of the N-terminal half of the A-T gene product which, together with the previously published C-terminal half, completes the sequence of the A-T protein. No homologies with other genes have been found within the N-terminal half of the A-T protein. We have also identified six mutations affecting the N-terminal half of the protein. One of these mutations was found to be associated with a haplotype that is common to four apparently unrelated families of Irish descent. All the patients so far examined for both A-T alleles were shown to be compound heterozygotes. None of these mutations affected a putative promoter region which may direct divergent transcription of both the A-T gene and a novel gene E14. The ability to recognise mutations across the entire coding sequence of the A-T gene provides a practical advantage to A-T families since a DNA based prenatal diagnosis will be possible in families where the mutations are identified irrespective of the level of radiosensitivity in these families.
Hum Mol Genet 1996 Jan
PMID:Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia. 878 52

Expansion of trinucleotide CAG repeats coding for polyglutamine has been implicated in five neurodegenerative disorders, including spinocerebellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II. We now have screened a large series of patients with ADCA or isolated cases with cerebellar ataxia, for the presence of proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected in 16 out of 40 families with ADCA type I. This corresponds to 24% of all ADCA type I families, which is much more frequent than SCA1 in this series of patients (13%). The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation. The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families. In addition, a specific 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II. It was also visualized in the cerebral cortex of one of the patients, demonstrating its translation in the nervous system. Finally, no new disease-related proteins containing expanded polyglutamine tracts could be detected in lymphoblasts from the remaining patients with ADCA or isolated cases with cerebellar ataxia.
Hum Mol Genet 1996 Dec
PMID:Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. 896 39

Several human Mendelian diseases, including the long-QT syndrome, malignant hyperthermia, and episodic ataxia/myokymia syndrome, have recently been demonstrated to be due to mutations in ion channel genes. Systematic mapping of ion channel genes may therefore reveal candidates for other heritable disorders. In this study, the GenBank and dbEST databases were used to identify members of several ion channel families (voltage-gated calcium and sodium, cardiac chloride, and all classes of potassium channels). Genes and ESTs without prior map localization were identified based on GDB and OWL database information and 15 genes and ESTs were selected for mapping. Of these 15, only the serotonin receptor 5HT3R had been previously mapped to a chromosome. A somatic cell hybrid panel (SCH) was screened with an STS from each gene and, if necessary the results verified by a second SCH panel. For three ESTs, rodent derived PCR products of the same size as the human STS precluded SCH mapping. For these three, human P1 clones were isolated and the genomic location was determined by metaphase FISH. These genes and ESTs can now be further evaluated as candidate genes for inherited cardiac, neuromuscular and psychiatric disorders mapped to these chromosomes. Furthermore, the ESTs developed in this study can be used to isolate genomic clones, enabling the determination of each transcript's genomic structure and physical map location. This approach may also be applicable to other gene families and may aid in the identification of candidate genes for groups of related heritable disorders.
Somat Cell Mol Genet 1996 Sep
PMID:Chromosomal localization of 15 ion channel genes. 903 51

Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional beta-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of beta-gal mRNA and totally deficient in GM1-ganglioside-hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff-positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulation of GM1-ganglioside in the brain progressed from twice to almost five times the normal amount during the period from 3 weeks to 3.5 months. Despite the accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice show no overt clinical phenotype up to 4-5 months. However, tremor, ataxia and abnormal gait become apparent in older mice. Thus, the beta-gal-deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.
Hum Mol Genet 1997 Feb
PMID:Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase. 906 40

Iraqi-Jewish optic atrophy plus is an autosomal recessive condition characterized by infantile optic atrophy, an early onset movement disorder, and 3-methylglutaconic aciduria. Other features include spastic paraplegia, mild ataxia, mild cognitive deficiency and dysarthria. This disorder was identified in inbred Iraqi-Jewish kindreds in which relationships between most of the affected individuals were unknown. In this study we identify linkage to chromosome 19q13.2-q13.3 by using a DNA pooling strategy to perform a genome wide screen followed by a high density search for shared segments among affected individuals in candidate regions identified in the initial genome wide screen. A significantly high positive lod score of 6.14 at zero recombination was obtained for the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. The existence of multiple recombinant individuals indicates the disease interval can be further narrowed with additional markers. Linkage disequilibrium was seen in six polymorphic markers across a 1 Mb interval. This region is well characterized and contains several candidate genes.
Hum Mol Genet 1997 Apr
PMID:Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. 909 59

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

Purkinje cells are uniquely susceptible to a number of physical, chemical, and genetic insults both during development and in the mature state. We have previously shown that when the postmitotic state of murine Purkinje cells is altered by inactivation of the retinoblastoma tumor susceptibility protein (pRb), immature as well as mature Purkinje cells undergo apoptosis. DNA synthesis and neuronal loss are induced in postmitotic Purkinje cells dependent upon the pRb-binding portion of SV40 large T antigen (T-ag). In the present study, Purkinje cell targeting of a mutant T-ag, PVU, which does not bind pRb, reveals disparate cerebellar phenotypes dependent upon temporal differences in transgene expression. Strong embryonic and postnatal transgene expression in three lines alters Purkinje cell development and function during the second postnatal week, causing ataxia without Purkinje cell loss. In contrast, two other transgenic lines reveal that PVU T-ag expression following normal Purkinje cell maturation causes rapid Purkinje cell degeneration. The second and third postnatal weeks of cerebellar development, which include the major period of synaptogenesis, appear to be the defining stage for the two PVU-induced phenotypes. These data indicate that Purkinje cell death susceptibility varies with developmental stage.
Mol Cell Neurosci 1997 Jan
PMID:Susceptibility to cell death induced by mutant SV40 T-antigen correlates with Purkinje neuron functional development. 920 79


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