Silent exonic mutation in the acid-α-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing

Glycogen-storage disease type II (GSDII) is an autosomal recessive disorder caused by a deficiency of acid a-glucosidase (GAA). The residual GAA activity is largely related to the severity of the clinical course. Most patients with infantile-onset GSDII do not show any enzyme activity, whereas patients with the late-onset forms of GSDII show various degrees of GAA activity. We performed a molecular genetic study on a Japanese boy with childhood-onset GSDII. The patient was a compound heterozygote for a newly discovered splice-site c.546G>T mutation and a recurrent missense p.R600C mutation, which usually causes the fatal infantile form in a homozygous state. The c.546G>T mutation, which did not alter the amino-acid sequence, was positioned at the last base of exon 2. cDNA-sequencing analysis revealed that c.546G>T was a leaky splice mutation, leading to the production of a normally spliced transcript, which was responsible for the low-level (approximately 10%) expression of the active enzyme in the patient's fibroblasts. Journal of Human Genetics (2009) 54, 493-496; doi: 10.1038/jhg.2009.66; published online 17 July 2009