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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



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ID: 533752.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon.
Authors:Musante, Luciana; Kunde, Stella-Amrei; Sulistio, Tina O.; Frints, Suzanna G.M.; Schwartz, Charles E.; Martínez, Francisco; Romano, Corrado; Ropers, Hans-Hilger; Kalscheuer, Vera M.; Fischer, Ute; Grimme, Astrid
Language:English
Date of Publication (YYYY-MM-DD):2010-01-01
Title of Journal:Human Mutation
Journal Abbrev.:Hum. Mut.
Volume:31
Issue / Number:1
Start Page:90
End Page:98
Copyright:© 2009 Wiley-Liss, Inc.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Free Keywords:XLMR;
PQBP1;
splicing;
PTC;
NMD;
NAS
Comment of the Author/Creator:Email: Vera M. Kalscheuer (kalscheu@molgen.mpg.de)
Correspondence: Vera M. Kalscheuer, Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Clinical Genetics, University Hospital azM
Institute for Growth and Development, GROW, Maastricht University, Maastricht, The Netherlands;
2.JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA;
3.Unidad de Genética, Hospital Universitario La Fe, Valencia, Spain;
4.Unità Operativa Complessa di Pediatria e Genetica Medica, IRCCS Associazione Oasi Maria Santissima, Troina (Enna), Italy.
Identifiers:URL:http://onlinelibrary.wiley.com/doi/10.1002/humu.21...
ISSN:1059-7794
DOI:10.1002/humu.21146
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