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  Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon.

Musante, L., Kunde, S.-A., Sulistio, T. O., Frints, S. G., Schwartz, C. E., Martínez, F., et al. (2010). Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon. Human Mutation, 31(1), 90-98. doi:10.1002/humu.21146.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7C2A-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7C2B-1
Genre: Journal Article
Alternative Title : Hum. Mut.

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 Creators:
Musante, Luciana1, Author              
Kunde, Stella-Amrei2, Author
Sulistio, Tina O.2, Author
Frints, Suzanna G.M., Author
Schwartz, Charles E., Author
Martínez, Francisco, Author
Romano, Corrado, Author
Ropers, Hans-Hilger3, Author              
Kalscheuer, Vera M.4, Author              
Fischer, Ute4, Author              
Grimme, Astrid4, Author              
Affiliations:
1Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479644              
2Max Planck Society, ou_persistent13              
3Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
4Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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Free keywords: XLMR; PQBP1; splicing; PTC; NMD; NAS
 Abstract: The polyglutamine binding protein 1 (PQBP1) gene plays an important role in X-linked mental retardation (XLMR). Nine of the thirteen PQBP1 mutations known to date affect the AG hexamer in exon 4 and cause frameshifts introducing premature termination codons (PTCs). However, the phenotype in this group of patients is variable. To investigate the pathology of these PQBP1 mutations, we evaluated their consequences on mRNA and protein expression. RT-PCRs revealed mutation-specific reduction of PQBP1 mRNAs carrying the PTCs that can be partially restored by blocking translation, thus indicating a role for the nonsense-mediated mRNA decay pathway. In addition, these mutations resulted in altered levels of PQBP1 transcripts that skipped exon 4, probably as a result of altering important splicing motifs via nonsense-associated altered splicing (NAS). This hypothesis is supported by transfection experiments using wild-type and mutant PQBP1 minigenes. Moreover, we show that a truncated PQBP1 protein is indeed present in the patients. Remarkably, patients with insertion/deletion mutations in the AG hexamer express significantly increased levels of a PQBP1 isoform, which is very likely encoded by the transcripts without exon 4, confirming the findings at the mRNA level. Our study provides significant insight into the early events contributing to the pathogenesis of the PQBP1 related XLMR disease. Hum Mutat 31:90–98, 2010.

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Language(s): eng - English
 Dates: 2010-01-01
 Publication Status: Published in print
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Title: Human Mutation
  Alternative Title : Hum. Mut.
Source Genre: Journal
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Pages: - Volume / Issue: 31 (1) Sequence Number: - Start / End Page: 90 - 98 Identifier: ISSN: 1059-7794