Human Molecular Genetics, Vol 5, 995-1000, Copyright © 1996 by Oxford University Press
N Raben, RC Nichols, F Martiniuk and PH Plotz
Glycogenosis type II is a recessively inherited disorder caused by
mutations in the acid maltase (GAA) gene. Clinically, three different
phenotypes are recognized: Infantile, juvenile and adult forms. A majority
of compound heterozygous adult-onset patients carry a t-13g mutation in
intron 1 associated with splicing out the first coding exon (exon 2). We
have studied the mechanism of this mutation in a model system with
wild-type and mutant minigenes expressed in a GAA deficient cell line. We
have demonstrated that the mutation does not prevent normal splicing; low
levels of correctly spliced mRNA are generated with the mutant construct.
The data explain why the mutation is restricted to a milder, adult-onset
phenotype. We also demonstrate that splicing out of exon 2 occurs with the
wild-type construct, and thus represents alternative splicing which takes
place in normal cells. Three splice variants (SV1, SV2 and SV3) are made
with both the mutant and the wild-type constructs. Furthermore, as shown by
RNAse protection assay, these mRNA variants are less abundant with the
mutant construct. Thus, a major effect of the mutation appears to be a low
splicing efficiency, since the total amount of all the transcripts
generated from the mutant construct is reduced compared with the wild type.
The removal of approximately 90% of the intron 1 (2.6 kb) sequence resulted
in a dramatic increase in the levels of correctly spliced mRNA, indicating
that the intron may contain a powerful transcriptional repressor.
ARTICLES
A model of mRNA splicing in adult lysosomal storage disease (glycogenosis type II)
Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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