Heterogeneous mutations in the glycogen-debranching enzyme gene are responsible for glycogen storage disease type IIIa in Japan

Abstract

Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disorder caused by deficiency of the glycogen-debranching enzyme (AGL). Recent studies of the AGL gene have revealed the prevalent mutations in North African Jewish and Caucasian populations, but whether these common mutations are present in other ethnic groups remains unclear. We have investigated eight Japanese GSD IIIa patients from seven families and identified seven mutations, including one splicing mutation (IVS 14+1G-->T) previously reported by us, together with six novel ones: a nonsense mutation (L124X), a splice site mutation (IVS29-1G-->C), a 1-bp deletion (587delC), a 2-bp deletion (4216-4217delAG), a 1-bp insertion (2072-2073insA), and a 3-bp insertion (4735-4736insTAT). The last mutation results in insertion of a tyrosine residue at a putative glycogen-binding site, and the rest are predicted to cause synthesis of truncated proteins lacking the glycogen-binding site at the carboxyl terminal. Thirteen novel polymorphisms have also been revealed in this study: three amino acid substitutions (R387Q, G1115R, and E1343 K), one silent point mutation (L298L), one nucleotide change in the 5'-noncoding region, and eight nucleotide changes in introns. Haplotype analysis with combinations of these polymorphic markers showed L124X, IVS14+1G-->T, and 4216-4217delAG to be on different haplotypes. These results demonstrate the importance of the integrity of the carboxy terminal domain in the AGL protein and the molecular heterogeneity of GSD IIIa in Japan.

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

“…Haplotype determination in the AGL gene Twenty-three polymorphic markers in the AGL gene were genotyped in accordance with previous reports (Horinishi et al 2000(Horinishi et al , 2002Okubo et al 2000b;Shen et al 1997).…”

“…The full coding exons, their relevant exonintron boundaries, and the 5¢-and 3¢-flanking regions of the patients' AGL gene were sequenced directly as has been described previously (Okubo et al 2000b). The nucleotides of AGL cDNA were numbered according to AGL isoform 1 (GenBank accession no.…”

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

“…The full coding exons, their relevant exon-intron boundaries and the 5¢-and 3¢-flanking regions of the patients' AGL were sequenced directly, as described previously. 13 The nucleotides of AGL cDNA were numbered according to AGL isoform 1 (GenBank accession no. NM_000642).…”

Molecular characterization of Egyptian patients with glycogen storage disease type IIIa

“…The full coding exons, their relevant exon-intron boundaries, and the 5¢-and 3¢-flanking regions of the patients' AGL genes were sequenced directly as described previously (Okubo et al 2000b). The nucleotides of AGL cDNA were numbered according to AGL isoform 1 (GenBank accession no.…”