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
Source: PubMed
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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.
    Journal of Human Genetics 10/2009; 54(11):681-6. DOI:10.1038/jhg.2009.100 · 2.46 Impact Factor
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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.
    Journal of Human Genetics 11/2011; 57(3):170-5. DOI:10.1038/jhg.2011.122 · 2.46 Impact Factor
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    ABSTRACT: Glycogen storage disease type III (GSD III; MIM #232400) is an autosomal recessive inherited disorder characterized by fasting hypoglycemia, growth retardation, hepatomegaly, progressive myopathy, and cardiomyopathy. GSD III is caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL). Molecular analyses of AGL have indicated heterogeneity depending on ethnic groups. In Turkey we reported 13 different AGL mutations from GSD III patients in the Eastern region; however, the full spectrum of AGL mutations in Turkish population remains unclear. Here we investigated 12 GSD III patients mostly from Western Turkey. The full coding exons, their relevant exon-intron boundaries, and the 5'- and 3'-flanking regions of the patients' AGL were sequenced. AGL haplotypes were determined. Splicing mutations were characterized by RNA transcript analysis. Twelve different mutations were identified: 7 novel AGL mutations [69-base pair deletion (c.1056_1082+42del69), 21-base par deletion (c.3940_3949+11del21), two small duplications (c.364_365dupCT and c.1497_1500dupAGAG), and 3 splicing mutations (c.1736-11A>G, c.3259+1G>A and c.3588+2T>G)], along with 5 known mutations (c.1019delA, c.958+1G>A, c.4161+5G>A, p.R864X and p.R1218X). Transcripts of splicing mutations (c.1736-11A>G, c.3588+2T>G and c.4161+5G>A) were shown to cause aberrant splicing. AGL haplotype analyses suggested that c.1019delA and c.958+1G>A are founder mutations in Turkish patients, while p.R864X is a recurrent mutation. Our study broadens the spectrum of AGL mutations and demonstrates that mutations in Western Turkey are different from those in the Eastern region. Copyright © 2014 Elsevier B.V. All rights reserved.
    Clinica Chimica Acta 01/2015; 439:162-7. DOI:10.1016/j.cca.2014.10.016 · 2.82 Impact Factor