Novel AGL mutation in a Turkish patient with glycogen storage disease type IIIa

Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Minato-ku, Tokyo, Japan.
Pediatrics International (Impact Factor: 0.73). 02/2010; 52(1):145-7. DOI: 10.1111/j.1442-200X.2009.02943.x
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Available from: Toshio Murase, Jan 06, 2016
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    ABSTRACT: Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL) with two enzyme activities: transferase and glucosidase. A missense mutation causing isolated glucosidase deficiency has never been reported. In this study, we examined 23 patients of Turkish ancestry and identified a novel missense mutation p.R1147G with isolated glucosidase deficiency, along with nine AGL mutations: six nonsense mutations (p.W373X, p.R595X, p.Q667X, p.Q1205X, p.W1327X and p.Q1376X), one deletion (c.1019delA) and two splicing mutation (c.293+2T>G and c.958+1G>A). As p.R1147G impaired glucosidase activity, but maintained transferase activity in vitro, a 12-year-old girl homozygous for p.R1147G was diagnosed with having isolated glucosidase deficiency. Of nine other mutations, p.W1327X and c.1019delA were recurrent, whereas seven mutations were novel. Six patients with p.W1327X were all from two nearby cities on the East Black Sea and shared the same AGL haplotype, indicating a founder effect in Turkish patients. Patients with the same mutations had identical haplotypes. Our results provide the first comprehensive overview of clinical and molecular features of Turkish GSD III patients and the first description of the missense mutation associated with isolated glucosidase deficiency.
    Full-text · Article · Oct 2009 · Journal of Human Genetics
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    ABSTRACT: Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.
    No preview · Article · Nov 2011 · Journal of Human Genetics
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    ABSTRACT: Aim: AGL gene mutations are responsible for glycogen storage disease type Ill which is an autosomal recessive disorder. The distribution of these mutations shows a great variance in different populations. The aim of this study is to uncover the AGL gene mutation profile among Turkish patients and to contribute to the establishment of a link between these mutations and the clinical picture of the disease. Material and Method: A total of ten patients aged between two and eight years (mean age 1.7+1.1) who were diagnosed with glycogen storage disease type III by liver biopsy and enzymatic analysis from eight different families were included in this study. DNA was isolated from the peripheral blood samples of these patients and exons 6, 7, 9-18, 22, 24, 29-34 of the AGL gene were studied by DNA sequencing analysis. Results: Our study revealed two novel missense mutations p.G167V and p.Y173E two novel intronic single base substitutions c.1284-1G>A and c.2002-2A>T and a known single base substitution p.W1327X. Numerous intronic variants were also identified. As a result of the analysis of ten patients, SNP's rs3736296, IVS12-197T>G, rs2291637, rs2035961, rs2274570, rs6692695, rs296885 were found in 1, 6, 1, 1, 1, 1, and 2 of the 10 patients, respectively. Conclusions: According to the recent literature about the AGL gene which is constituted of a total of 35 coding exons, mutations have been reported frequently in exons 3, 4, 7, 16, 21, 25, 30 and 31. This study and previous studies reveal that the majority of the mutations identified in Turkish patients so far have been detected in exon 31 of the AGL gene. In addition, the distribution of AGL gene mutations in Turkish patients reflects the genetic heterogeneity in our population. (Turk Arch Ped 2012; 47:278-82)
    No preview · Article · Dec 2012 · Turk Pediatri Arsivi
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