A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families

BACKGROUND AND OBJECTIVES: Glycogen storage disease type 3 (GSD III) is an autosomal recessive disorder caused by genetic mutations in the gene AGL. AGL encodes amylo-α-1, 6-glucosidase, 4-α-glucanotransferase, a glycogen debranching enzyme. GSD III is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy, and cardiomyopathy due to storage of abnormally structured glycogen in both skeletal and cardiac muscles and/or liver. The aim of this study is to detect mutations underlying GSD III in Saudi patients. DESIGN AND SETTINGS: A cross-sectional clinical genetic study of 5 Saudi consanguineous families examined at the metabolic clinic of the Madinah Maternity and Children Hospital. PATIENTS AND METHODS: We present a biochemical and molecular analysis of 5 consanguineous Saudi families with GSD III. DNA was isolated from the peripheral blood of 31 individuals, including 12 patients, and the AGL gene was sequenced bidirectionally. DNA sequences were compared with the AGL reference sequence from the ensemble genome browser. RESULTS: Genotyping and sequence analysis identified a homozygous intronic splice acceptor site mutation (IVS32-12A>G) in 4 families perfectly segregating with the phenotype. Complementary (c)DNA sequence analysis of the AGL gene revealed an 11-bp sequence insertion between exon 32 and exon 33 due to the creation of a new 3′ splice site. The predicted mutant enzyme was truncated by 112 carboxyl-terminal amino acids as a result of premature termination. CONCLUSION: Haplotype analysis revealed that the mutation arises as a result of founder effect, not an independent event. This is the first report of a genetic mutation in the AGL gene from Saudi Arabia. Screening for this mutation can improve genetic counseling and prenatal diagnosis of GSD III in Saudi Arabia.