Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III

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 (IVS32-12A4G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.

Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

“…Eight genetic diseases belong to this category. This is the case for 11-β hydroxylase deficiency [62,63], hereditary breast and ovarian cancer [64,65], cystic fibrosis [66,67], glycogen storage disease type III [68,69], Leber congenital amaurosis [70], leukocyte adhesion deficiency [71,72] and MDM [Charfeddine C, personal communciation, 37,73]. For some founder mutations, the situation is relatively complex.…”

Molecular and clinical delineation of 12 patients with glycogen storage disease type III in Western Turkey

“…As a result, haplotypes are different, indicating that the same mutation occurred independently. In addition, SNP-10 in exon 3 (rs2307130) in Tunisian patient reported by Mili et al [18] was different from patient 12. Also, nonsense mutation p.R1218X (c.3652 CNT) was reported in two patients of Mediterranean origin [20].…”

“…A nonsense mutation p.R864X (c.2590CNT) is one of the most prevalent mutations in Caucasian GSD IIIa patients [16] and we found that this mutation is present in a Turkish patient. R864X has been reported in GSD III patients in Italia [17] and Tunisia [18] as well. By using the haplotype study in Chinese and Faroese GSD III patients, Lam et al demonstrated that p.R408X is a recurrent mutation [19].…”

A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series

“…Phenotypic variation is common among patients with different genotypes who have glycogen storage disease type IIIa. 1,3,11,16,17 In adults, the condition may only be diagnosed late once hepatomegaly, cirrhosis, hepatic carcinoma, cardiomyopathy or neuro-muscular dysfunction has developed. 18 Clinical variability among patients with the same mutation could be related to the age at diagnosis, compliance with dietary recommendations, environment or unknown modifying genes.…”