کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10834440 | 1065890 | 2008 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
GM1 gangliosidosis is an inherited, fatal neurodegenerative disease caused by deficiency of lysosomal β-d-galactosidase (EC 3.2.1.23) and consequent storage of undegraded GM1 ganglioside. To characterize the genetic mutation responsible for feline GM1 gangliosidosis, the normal sequence of feline β-galactosidase cDNA first was defined. The feline β-galactosidase open reading frame is 2010 base pairs, producing a protein of 669 amino acids. The putative signal sequence consists of amino acids 1-24 of the β-galactosidase precursor protein, which contains seven potential N-linked glycosylation sites, as in the human protein. Overall sequence homology between feline and human β-galactosidase is 74% for the open reading frame and 82% for the amino acid sequence. After normal β-galactosidase was sequenced, the mutation responsible for feline GM1 gangliosidosis was defined as a G to C substitution at position 1448 of the open reading frame, resulting in an amino acid substitution at arginine 483, known to cause GM1 gangliosidosis in humans. Feline β-galactosidase messenger RNA levels were normal in cerebral cortex, as determined by quantitative RT-PCR assays. Although enzymatic activity is severely reduced by the mutation, a full-length feline β-galactosidase cDNA restored activity in transfected GM1 fibroblasts to 18-times normal. β-Galactosidase protein levels in GM1 tissues were normal on Western blots, but immunofluorescence analysis demonstrated that the majority of mutant β-galactosidase protein did not reach the lysosome. Additionally, GM1 cat fibroblasts demonstrated increased expression of glucose-related protein 78/BiP and protein disulfide isomerase, suggesting that the unfolded protein response plays a role in pathogenesis of feline GM1 gangliosidosis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Genetics and Metabolism - Volume 94, Issue 2, June 2008, Pages 212-221
Journal: Molecular Genetics and Metabolism - Volume 94, Issue 2, June 2008, Pages 212-221
نویسندگان
Douglas R. Martin, Brigitte A. Rigat, Polly Foureman, G.S. Varadarajan, Misako Hwang, Barbara K. Krum, Bruce F. Smith, John W. Callahan, Don J. Mahuran, Henry J. Baker,