Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey

Abstract

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and/or muscles and caused by deficiency in the glycogen debranching enzyme (AGL). Previous studies have revealed that the spectrum of AGL mutations in GSD III patients depends on ethnic grouping. We investigated nine GSD III patients from Germany, Canada, Afghanistan, Iran, and Turkey and identified six novel AGL mutations: one nonsense (W255X), three deletions (1019delA, 3202-3203delTA, and 1859-1869del11-bp), and two splicing mutations (IVS7 + 5G > A and IVS21 + 5insA), together with three previously reported ones (R864X, W1327X, and IVS21 + 1G > A). All mutations are predicted to lead to premature termination, which abolishes enzyme activity. Our molecular study on GSD III patients of different ethnic ancestry showed allelic heterogeneity of AGL mutations. This is the first AGL mutation report for German, Canadian, Afghan, Iranian and Turkish populations.

Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations

“…RFLP analysis with EcoRI, as described previously, 16 showed that patients 18 and 19 were homozygotes and patient 20 was heterozygote for c.1019delA. Sequencing analysis did not detect the other mutation of patient 20.…”

“…RFLP analyses to detect p.W1327X and c.1019delA were described previously. 16,19 Besides, a pair of primers (Table 2) were used for PCR and each specific restriction endonuclease was added to digest PCR products. Restriction digests were analyzed on a polyacrylamide gel.…”

“…16 SNPs numbers were cited according to database of Single Nucleotide Polymorphisms (dbSNP Build 130) available from http:// www.ncbi.nlm.nih.gov/SNP/.…”

“…In ethnic groups with high rate of consanguinity, prevalent mutations have been reported. For example, specific mutations are prevalent in North African Jewish population and in an 16 along with one deletion (c.2474delC). 17 To investigate further molecular characteristic in Turkey, we examined 23 new cases with Turkish GSD III.…”

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

“…Similarly, the two others heterozygote mutations: nonsense mutation W255X in exon 7 is predicted to cause a truncated enzyme lacking the glycogen-binding site in the carboxyl terminal 34 and R524H mutation, located in exon 13, is also known to alter the catalytic function of the transferase domain. 35 The three novel mutations, Y1148X, 3033_3036del AATT and 3216-3217del GA, were predicted to lead to a premature stop codon, respectively, at positions 1148, 1037 and 1119 and abolishing the enzyme activity.…”