title: HnRNP A1 and A/B interaction with PABPN1 in oculopharyngeal muscular dystrophy.
abstract: BACKGROUND
  Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive ptosis, dysphagia and proximal limb weakness. The autosomal dominant form of this disease is caused by short expansions of a (GCG)6 repeat to (GCG) in the PABPN1 gene. The mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminus of PABPN1. The mutated PABPN1 (mPABPN1) induces the formation of intranuclear filamentous inclusions that sequester poly(A) RNA and are associated with cell death.
  
  
  METHODS
  Human fetal brain cDNA library was used to look for PABPNI binding proteins using yeast two-hybrid screen. The protein interaction was confirmed by GST pull-down and co-immunoprecipitation assays. Oculopharyngeal muscular dystrophy cellular model and OPMD patient muscle tissue were used to check whether the PABPN1 binding proteins were involved in the formation of OPMD intranuclear inclusions.
  
  
  RESULTS
  We identify two PABPNI interacting proteins, hnRNP A1 and hnRNP A/B. When co-expressed with mPABPN1 in COS-7 cells, predominantly nuclear protein hnRNP A1 and A/B co-localize with mPABPN1 in the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions.
  
  
  CONCLUSIONS
  The hnRNP proteins are involved in mRNA processing and mRNA nucleocytoplasmic export, sequestering of hnRNPs in OPMD intranuclear aggregates supports the view that OPMD intranuclear inclusions are "poly(A) RNA traps", which would interfere with RNA export, and cause muscle cell death.
authors.affiliation: Center for Research in Neuroscience, McGill University, Montreal, Quebec, Canada.
authors.forename: Xueping
authors.initials: X
authors.lastname: Fan
authors.forename: Christiane
authors.initials: C
authors.lastname: Messaed
authors.forename: Patrick
authors.initials: P
authors.lastname: Dion
authors.forename: Janet
authors.initials: J
authors.lastname: Laganiere
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.forename: George
authors.initials: G
authors.lastname: Karpati
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D039141:Muscular Dystrophy, Oculopharyngeal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D039103:Poly(A)-Binding Protein II / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011233:Precipitin Tests; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009687:Nuclear Proteins; D010455:Peptides; D039103:Poly(A)-Binding Protein II; C019529:polyalanine