کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10833957 | 1065836 | 2011 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A novel mucopolysaccharidosis type I associated splice site mutation and IDUA splice variants
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کلمات کلیدی
qPCRPTCGAGsIDUAα-L-iduronidaseHSCTMPS IMucopolysaccharidosis type I - Mucopolysaccharidosis نوع IQuantitative PCR - PCR کمیenzyme replacement therapy - آنزیم جایگزین درمانmutation - جهشDermatan sulfate - سولفات درماتانMucopolysaccharidosis I - موکوپلیساکاریدوز IERT - هستندHeparan sulfate - هپاران سولفاتRNA splicing - پلاسر RNAHematopoietic stem cell transplantation - پیوند مغز استخوانpremature termination codon - کدون از بین بردن زودرسGlycosaminoglycans - گلیکوز آمینو گلیکان ها
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
Mucopolysaccharidosis type I is an autosomal recessive disorder caused by deficiency of α-l-iduronidase, encoded by the IDUA gene. More than 100 disease causing mutations have been reported in the gene, resulting in a wide range of phenotypes. Here we describe a previously unreported IDUA splice site mutation (NG_008103.1:g.21632G>C; NM_000203.3:c.1727+3G>C) causing a Hurler phenotype in a patient heterozygous for the common p.Q70X (NG_008103.1:g.5862C>T) mutation. Sequence analysis of IDUA transcripts demonstrated that the g.21632G>C mutation results in aberrant splicing of intron 12 (NM_000203.3:c.1727_1728insGTCC), introducing a frame shift and premature termination codon (NP_000194.2:p.Cys577SerfsX15). Gene expression studies suggest that the deleterious effect of the mutation is primarily due to a C-terminal truncation of the encoded polypeptide. Furthermore, we observed that both normal and mutant IDUA alleles give rise to alternatively spliced transcripts in leukocytes. Exclusion of exon 4 appeared to be the predominant alternative splicing event, probably resulting in polypeptides lacking iduronidase activity. The Hurler patient demonstrated exon 4 skipping in 5.6% of IDUA transcripts, while exon 4 skipping ranged 25-34% of transcripts among healthy individuals (n = 5). Alternative splicing might represent a mechanism for regulation of this enzyme, and the lower level of exon 4 skipping in the patient might be a response to intracellular accumulation of iduronidase substrates. Molecular characterization of IDUA mutations and splicing may assist early prediction of mucopolysaccharidosis type I phenotypes and increase the understanding of disease mechanisms. This is important considering the choice of current treatment options and for the development of future therapies.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Genetics and Metabolism - Volume 104, Issue 3, November 2011, Pages 289-294
Journal: Molecular Genetics and Metabolism - Volume 104, Issue 3, November 2011, Pages 289-294
نویسندگان
Sara Bremer, Annika Ohlsson, Else Brodtkorb, Helge Rootwelt, Terje Rootwelt, Berit Woldseth, Lars Mørkrid,