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

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.
AuthorsLuciana Musante, Stella-Amrei Kunde, Tina O Sulistio, Ute Fischer, Astrid Grimme, Suzanna G M Frints, Charles E Schwartz, Francisco Martínez, Corrado Romano, Hans-Hilger Ropers, Vera M Kalscheuer
JournalHuman mutation (Hum Mutat) Vol. 31 Issue 1 Pg. 90-8 (Jan 2010) ISSN: 1098-1004 [Electronic] United States
PMID19847789 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Codon, Nonsense
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PQBP1 protein, human
  • RNA, Messenger
Topics
  • Carrier Proteins (genetics, metabolism)
  • Cell Line
  • Codon, Nonsense
  • DNA-Binding Proteins
  • Exons (genetics)
  • Fibroblasts
  • Humans
  • Lymphocytes
  • Mental Retardation, X-Linked (genetics, pathology)
  • Mutation
  • Nuclear Proteins (genetics, metabolism)
  • RNA Stability
  • RNA, Messenger (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction

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