Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic studies of alcoholics, their families and controls have given credence to the idea that genetic influences in alcoholism exist, and set the stage for efforts to identify alcoholism-susceptibility genes (Devor and Cloninger, 1989). My purpose is not to review the genetics of alcoholism, but rather to review the genetic approaches that have been successful in identifying the genes responsible for genetic conditions such as muscular dystrophy and cystic fibrosis. In these disorders our current knowledge of the basic biochemical defect was derived directly from the cloning of the gene that is defective in the disorder. The cloned gene provides DNA probes for carrier identification and prenatal diagnosis, while knowledge of the basic defect allows new and direct investigation of potential therapeutic strategies. The genetic approach is much less definitive when it comes to the study of polygenic or multifactorial disorders such as schizophrenia or Alzheimer's disease. In the case of alcoholism the problem is exacerbated not only by environmental factors but also by phenotypic and genetic heterogeneity. The lack of a clear inheritance pattern means that plausible modes of inheritance must be invoked and tested on families with multiple affected members. Direct segregation analysis may not be possible and the less informative analysis of sib-pairs may be the method of choice. Ultimately, however, it should be possible to identify and clone those genes that play a major role in determining susceptibility to alcoholism. Once cloned, the protein products can be identified, and study of their function should lead to new understanding of the complex biological processes involved in this disorder.
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PMID:Molecular genetic approaches to the study of individual risk in alcoholism. 184 36

The time courses of changes in amplitudes of muscle action potentials (MAPs) obtained from gastrocnemius and soleus muscles by 5 Hz prolonged tibial nerve stimulation were studied. Subjects included muscular dystrophy (MD), spinal muscular atrophy, Issacs syndrome, idiopathic muscle spasms, psychiatric disorders such as autism and schizophrenia, and normal controls. In normal subjects, MAPs obtained at 5 minutes from gastrocnemius muscles was 87-102% of those at initiation of the stimulation. In soleus muscles, MAPs at 5 minutes was 95-105% of those at the beginning. In gastrocnemius muscles, MAPs increased in disorders such as Duchenne MD, Fukuyama type congenital MD, facioscapulohumeral MD, myotonic dystrophy, dermatomyositis, Kugelberg-Welander syndrome, viral myelitis, malignant hyperpyrexia, autism and schizophrenia. In soleus muscles, the increase of MAPs was demonstrated in Duchenne MD, Fukuyama type congenital MD, myotonic dystrophy and autism. MAPs remained within normal range in infants with Werdnig-Hoffman disease, Issacs syndrome and idiopathic muscle spasms. In two cases with Duchenne MD, MAPs obtained from gastrocnemius muscles reduced in amplitudes by the administration of dantrolen sodium. While the pathogenesis of the increased MAPs is not clear, several possible factors are discussed. It is considered that this 5 Hz examination may provide an important information for detecting the effect of dantrolen sodium on Duchenne MD, and it is also suggested that the examination will be a useful test for finding latent malignant hyperpyrexia.
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PMID:Increased muscle action potentials by 5 Hz prolonged nerve stimulation in neurological and neuromuscular disorders--clinical usefulness for detecting underlying pathophysiology. 648 78

We investigated the retroviral/retroposon hypothesis of schizophrenia by generating sequences with PCR primers based on a retroviral sequence recovered by Yee et al. [1998: Schizophr Res 29:92] from a cDNA library from postmortem brain tissue from an individual with psychosis in a genomic region (Xq21.3) that has been tentatively linked to schizophrenia and schizoaffective disorder by Laval et al. [1998: Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:420-427]. Within the block of homology with Yp that was generated by a transposition between the chimpanzee and Homo sapiens we find two sequences, HS307 and HS408, with a high degree of homology to but not identity with the schizophrenic brain cDNA. The closest match of these three sequences is to a family of retroposons, that has evolved from the HERV-K family of endogenous retroviruses, some members of which (e.g., SINE-R.C2) appear to be specific to the human genome. This element has been reported as a cause of Fukuyama-type muscular dystrophy [Kobayashi et al., 1998: Nature 394:388-392]. Such retroposons, as agents of change in the human genome, provide a strategy for investigating pathogenesis. On account of their genomic location in a region that has been subject to change in the course of hominid evolution, and that may have a relationship to psychosis and/or cerebral asymmetry, we conclude that these particular insertions deserve further investigation.
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PMID:SINE-R.C2 (a Homo sapiens specific retroposon) is homologous to CDNA from postmortem brain in schizophrenia and to two loci in the Xq21.3/Yp block linked to handedness and psychosis. 1049 Jul 17

The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.
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PMID:Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy. 1287 99

Dysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy. Subsequently, genetic studies have implicated variants of the human dysbindin-encoding gene, DTNBP1, in the pathogeneses of Hermansky-Pudlak syndrome and schizophrenia. The protein is a stable component of a multisubunit complex termed BLOC-1 (biogenesis of lysosome-related organelles complex-1). In the present study, the significance of the dystrobrevin-dysbindin interaction for BLOC-1 function was examined. Yeast two-hybrid analyses, and binding assays using recombinant proteins, demonstrated direct interaction involving coiled-coil-forming regions in both dysbindin and the dystrobrevins. However, recombinant proteins bearing the coiled-coil-forming regions of the dystrobrevins failed to bind endogenous BLOC-1 from HeLa cells or mouse brain or muscle, under conditions in which they bound the Dp71 isoform of dystrophin. Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms. Within BLOC-1, dysbindin is engaged in interactions with three other subunits, named pallidin, snapin and muted. We herein provide evidence that the same 69-residue region of dysbindin that is sufficient for dystrobrevin binding in vitro also contains the binding sites for pallidin and snapin, and at least part of the muted-binding interface. Functional, histological and immunohistochemical analyses failed to detect any sign of muscle pathology in BLOC-1-deficient, homozygous pallid mice. Taken together, these results suggest that dysbindin assembled into BLOC-1 is not a physiological binding partner of the dystrobrevins, likely due to engagement of its dystrobrevin-binding region in interactions with other subunits.
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PMID:Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. 1644 87

To determine the genetic basis of familial frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) we performed a clinical and genetic analysis of an affected family. A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD. Five others unaffected from the family were negative (all had less than 11 repeats). Because of the clinical and pathological overlap between FTLD and AD we performed a larger genome-wide association study and did not find association of single nucleotide polymorphisms (SNPs) in the C9ORF72 gene with Alzheimer's disease (AD) risk. Bioinformatic analysis of C9ORF72 using the Gene Expression Omnibus database showed expression differences in patients with muscular dystrophy, neural tube defects, and schizophrenia. We also report analysis of gene expression in brain regions using the Allen Human Brain Atlas. Defects in this recently reported gene are now believed to be the most common cause of inherited ALS and an important cause of inherited FTLD. Our work suggests that the gene may also be important in other neurological and psychiatric conditions.
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PMID:Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat. 2306 Aug 54

The first decades of the new medical genetics (1980 to 2000) were marked by resounding successes, with the identification of the genes responsible (when defective) for muscular dystrophy, cystic fibrosis, or Huntington's disease, to name justa few of the several thousand Mendelian genetic conditions whose causes are now known. In contrast, the search for genes involved in common disorders such as diabetes,hypertension, schizophrenia, or autism failed miserably in the 1990s, with inconsistent and conflicting results--although the strong genetic component of these diseases (that also involve environmental factors) was (and still is) beyond doubt. From 2000 on,thanks to huge progress in genomic knowledge, technology, and analytical methods, it became possible to reliably identify genes influencing the risk of complex conditions,using the so-called GWAS (Genome-Wide Association Study) approach. Yet many problems remain, such as the vexing question of the "missing heritability," or the difficulty of translating these scientific results into genetic tests with real clinical validity and utility. Autism is one of the cases in which a strong genetic component has been demonstrated, but where the search for causative genes remains difficult and attempts at developing valid genetic tests have failed, because of the many genes involved and possibly of the heterogeneity of the condition.
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PMID:Genes and non-mendelian diseases: dealing with complexity. 2534 6

Several diseases have been successfully modeled since the development of induced pluripotent stem cell (iPSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance have been optimized and many protocols for differentiating stem cell lines have been successfully developed, allowing the generation of several cellular subtypes in vitro. Gene editing technologies have also greatly advanced lately, enhancing disease-specific phenotypes by creating isogenic cell lines, allowing mutations to be corrected in affected samples or inserted in control lines. Neurological disorders have benefited the most from iPSC-disease modeling for its capability for generating disease-relevant cell types in vitro from the central nervous system, such as neurons and glial cells, otherwise only available from post-mortem samples. Patient-specific iPSC-derived neural cells can recapitulate the phenotypes of these diseases and therefore, considerably enrich our understanding of pathogenesis, disease mechanism and facilitate the development of drug screening platforms for novel therapeutic targets. Here, we review the accomplishments and the current progress in human neurological disorders by using iPSC modeling for Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, duchenne muscular dystrophy, schizophrenia and autism spectrum disorders, which include Timothy syndrome, Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, Phelan-McDermid, Rett syndrome as well as Nonsyndromic Autism.
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PMID:Induced pluripotent stem cells for modeling neurological disorders. 2672 48