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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
|
| pubmed:dateCreated |
1997-1-16
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jul
|
| pubmed:issn |
0964-6906
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
5
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
995-1000
|
| pubmed:dateRevised |
2004-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:8817337-Adult,
pubmed-meshheading:8817337-Age of Onset,
pubmed-meshheading:8817337-Alternative Splicing,
pubmed-meshheading:8817337-Cell Line, Transformed,
pubmed-meshheading:8817337-Exons,
pubmed-meshheading:8817337-Fibroblasts,
pubmed-meshheading:8817337-Gene Expression,
pubmed-meshheading:8817337-Glycogen Storage Disease Type II,
pubmed-meshheading:8817337-Humans,
pubmed-meshheading:8817337-Introns,
pubmed-meshheading:8817337-Point Mutation,
pubmed-meshheading:8817337-RNA, Messenger,
pubmed-meshheading:8817337-RNA Splicing,
pubmed-meshheading:8817337-Sequence Deletion
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
A model of mRNA splicing in adult lysosomal storage disease (glycogenosis type II).
|
| pubmed:affiliation |
Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
|
| pubmed:publicationType |
Journal Article
|