Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α(1A)-voltage-dependent calcium channel
TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Citations
More filters
TL;DR: It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.
Abstract: The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.
1,341 citations
TL;DR: A model for pathogenesis that illuminates the unifying features of these polyglutamine disorders is concluded, and may prove relevant to other neurodegenerative disorders as well.
Abstract: A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.
1,287 citations
TL;DR: The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent, and will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.
Abstract: Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.
939 citations
TL;DR: It is suggested that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.
823 citations
Cites background from "Autosomal dominant cerebellar ataxi..."
...…1994; Imbert et al., 1996; Lindblad et al., 1996; Pulst deep basal ganglia, the brainstem, the spinal cord, and, et al., 1996; Sanpei et al., 1996; Zhuchenko et al., 1997). to a lesser extent, the cerebellum (Sachdev et al., 1982; These disorders are thought to share a common patho- Yuasa et al.,…...
[...]
References
More filters
Book•
[...]
01 Jan 1989
TL;DR: To develop a program to print the barcodes using two commonly uses command sets and hence evaluates their ease of use for such applications, students should be able to program dot matrix printers, by manipulating bit level information and ink jet printers using page description language, such as PCL.
Abstract: 1. OBJECTIVE To develop a program to print the barcodes using two commonly uses command sets and hence evaluates their ease of use for such applications. Upon completion of this experiment, students should be able to program dot matrix printers, by manipulating bit level information and ink jet printers using page description language, such as PCL which uses raster image for graphics output. Students will also become familiar with the encoding and dimensional requirements of barcode symbologies, and the suitability of the selected printers for barcode printing. The Computer Engineering Laboratory is set up with IBM-compatible PC's installed with standard C compiler. The laboratory also has several kinds of printers for this experiment. They are classified into two groups. One group consists of dot-matrix printers and the other group consists of HP ink jet printers. In this experiment, each student will have to program a dot-matrix printer using Epson 9-pin graphics command codes in group A printers and HP PCL graphics commands for the ink jet printer in group B. The assignment of different printers is as follows: 4. INTRODUCTION Barcode labelling is widely implemented in the retail marketplace and is gaining increasing visibility in a broad range of non-retail applications. To read the information contained in a barcode symbol, a scanning device such as a wand can be used. As the scanning device is moved across the symbol, the width pattern of the bars and the spaces is analysed by the reading equipment and the original data is recovered. A number of barcodes has been developed over the years, these include UPS, interleaved 2 of 5, rationalised codabar, code 39, code 128, code 93 and code 49. The American format for article numbering is the Universal Product Code (UPC). The UPC has been successfully employed in the supermarket industry since 1973. It is designed to uniquely identify a product and its manufacturer. Refer to Appendix A for UPC specifications which are necessary for this experiment. Barcode symbols can be printed with various printing technologies and on a variety of substrate labels, tags and papers. In this experiment, plain paper will be used. Hence, the quality of printed barcode will only depend on the printing mechanism. In this experiment, students will learn to program dot matrix printers by manipulating bit level information. A brief summary of the commonly used commands is attached in Appendix B and abstract from the manuals …
8,170 citations
TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
7,224 citations
Journal Article•
TL;DR: The Huntington's disease mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
6,992 citations
TL;DR: Using the fully sequenced 1300 nucleotide-long bovine preproenkephalin mRNA, it is established by sequencing that the method yields faithful full-length transcripts.
4,214 citations
TL;DR: A fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes is identified and localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.
3,290 citations