کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5905986 | 1159945 | 2014 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form
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کلمات کلیدی
ASARMSDBMTTIMGalCerroot-mean-square distanceGloboid cell leukodystrophy - leukodystrophy سلول گلوبیدPsychosine - psychosineKrabbe Disease - بیماری خرچنگsolvent-accessible surface area - سطح قابل دسترس در دسترس حلالPhenotype - فنوتیپProtein processing - پردازش پروتئینBone marrow transplantation - پیوند مغز استخوانgalactocerebroside - گالاتوکروبروزیدGalactocerebrosidase - گالاکتروسروبروزیدازGalC - گالکسی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
ژنتیک
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Krabbe disease is an autosomal recessive leukodystrophy caused by the deficiency of the galactocerebrosidase (GALC) enzyme. It is pathologically characterized by demyelination of the central and peripheral nervous systems by accumulation of galactosylsphingosine. To date, more than 120 mutations in the GALC gene have been reported worldwide and genotype-phenotype correlations have been reported in some types of mutations. In this study, we analyzed 22 unreported Japanese patients with Krabbe disease and summarized a total of 51 Japanese patients, including 29 previously reported patients. To elucidate how GALC mutations impair enzymatic activity, multiple disease-causing mutations including common mutations and polymorphisms were investigated for enzymatic activity and precursor processing ability with transient expression system. We also performed 3-D enzyme structure analysis to determine the effect of each new mutation. Five novel mutations were detected including one deletion c.1808delT [p.L603X], one nonsense mutation c.1023C>G [p.Y341X], and three missense mutations c.209T>C [p.L70P], c.1054G>A [p.G352R], and c.1937G>C [p.G646A]. For the total of 51 patients, 59% had late-onset forms of Krabbe disease. Seven common mutations accounted for 58% of mutant alleles of patients with Krabbe disease in Japan. Infantile-onset mutations had almost no enzyme activity, while late-onset mutations had 4%-20% of normal enzyme activity. The processing rate of precursor GALC protein to mature form was slower for infantile-onset mutations. Heat stability of the mutant proteins revealed that p.G270D was more stable compared to the other mutations. The constructed 3D-model showed that the residues for Krabbe mutations were less solvent-accessible and located in the core region of GALC protein. In conclusion, we have demonstrated that the most common phenotype in Japan is the late-onset type, that the enzyme activity for GALC mutants is correlated with mutational severity, and that the most pathogenic factor is due to the processing rate from the precursor to the mature protein.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gene - Volume 534, Issue 2, 25 January 2014, Pages 144-154
Journal: Gene - Volume 534, Issue 2, 25 January 2014, Pages 144-154
نویسندگان
Mohammad Arif Hossain, Takanobu Otomo, Seiji Saito, Kazuki Ohno, Hitoshi Sakuraba, Yusuke Hamada, Keiichi Ozono, Norio Sakai,