A novel point mutation in an acceptor splice site of intron 32 (IVS32 A -12 →G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb

Abstract

Genetic deficiency of the glycogen-debranching enzyme (debrancher) causes glycogen storage disease type III (GSD III), which is divided into two subtypes: IIIa and IIIb. In GSD IIIb, glycogen accumulates only in the liver, whereas both liver and muscles are involved in GSD IIIa. The molecular basis for the differences between the two subtypes has not been fully elucidated. Recently, mutations in exon 3 of the debrancher gene were reported to be specifically associated with GSD IIIb. However, we describe a homozygous GSD IIIb patient without mutations in exon 3. Analysis of the patient's debrancher cDNA revealed an 11-bp insertion in the normal sequence. An A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS 32 A-12-->G) was identified in the patient's debrancher gene. No mutations were found in exon 3. Mutational analysis of the family showed the patient to be homozygous for this novel mutation as well as three polymorphic markers. Furthermore, the mother was heterozygous and the parents were first cousins. The acceptor splice site mutation created a new 3' splice site and resulted in insertion of an 11-bp intron sequence between exon 32 and exon 33 in the patient's debrancher mRNA. The predicted mutant enzyme was truncated by 112 amino acids as a result of premature termination. These findings suggested that a novel IVS 32 A-12-->G mutation caused GSD IIIb in this patient.

Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene

“…Patient 12 (female, age 41 years) had type IIIb and was compound heterozygous for the novel p.Arg343Trp mutation and c.4260-12A>G in intron 32. c.4260-12A>G was previously described and associated with IIIb as well as IIIa (Okubo et al 1998;Shaiu et al 2000). This patients' phenotype was severe IIIb and a case report on her was published after she received an orthotopic liver transplantation after being diagnosed with liver cirrhosis (Haagsma et al 1997).…”

Molecular characterization of Egyptian patients with glycogen storage disease type IIIa

“…We have reported the heterogeneity of AGL mutations in Japan. Eleven different mutations have been identified in our studies (Horinishi et al 2002;Okubo et al 1996Okubo et al , 1998Okubo et al , 1999Okubo et al , 2000a. Lucchiari et al (2002) discovered genetic heterogeneity in Italian patients also, although one splicing mutation (IVS21+1G>A) accounts for 28%.…”

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

“…Those studies revealed that the spectrum of AGL mutations in GSD III patients depends on ethnic grouping. For example, specific mutations were prevalent in Jewish GSD III patients (Parvari et al 1997) and in an isolated region such as the Faroe Islands (Santer et al 2001) because of founder effect, while heterogeneous mutations were found in Japanese patients (Horinishi et al 2002;Okubo et al 1996Okubo et al , 1998Okubo et al , 1999Okubo et al , 2000a. In Caucasian and Italian populations a few mutations accounted for a quarter of GSD III patients, but the rest of the mutations were heterogeneous (Lucchiari et al 2002a, b;Shen and Chen 2002).…”