title: HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA.
abstract: CHRNA1 gene, encoding the muscle nicotinic acetylcholine receptor alpha subunit, harbors an inframe exon P3A. Inclusion of exon P3A disables assembly of the acetylcholine receptor subunits. A single nucleotide mutation in exon P3A identified in congenital myasthenic syndrome causes exclusive inclusion of exon P3A. The mutation gains a de novo binding affinity for a splicing enhancing RNA-binding protein, hnRNP LL, and displaces binding of a splicing suppressing RNA-binding protein, hnRNP L. The hnRNP L binds to another splicing repressor PTB through the proline-rich region and promotes PTB binding to the polypyrimidine tract upstream of exon P3A, whereas hnRNP LL lacking the proline-rich region cannot bind to PTB. Interaction of hnRNP L with PTB inhibits association of U2AF(65) and U1 snRNP with the upstream and downstream of P3A, respectively, which causes a defect in exon P3A definition. HnRNP L and hnRNP LL thus antagonistically modulate PTB-mediated splicing suppression of exon P3A.
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Mohammad Alinoor
authors.initials: MA
authors.lastname: Rahman
authors.forename: Akio
authors.initials: A
authors.lastname: Masuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohe
authors.forename: Mikako
authors.initials: M
authors.lastname: Ito
authors.forename: David O
authors.initials: DO
authors.lastname: Hutchinson
authors.forename: Akila
authors.initials: A
authors.lastname: Mayeda
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D002460:Cell Line; D005091:Exons; D005786:Gene Expression Regulation; D023061:Gene Order; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D009045:Motor Endplate / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D055232:Proline-Rich Protein Domains; D011485:Protein Binding; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: C523021:CHRNA1 protein, human; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D012322:RNA Precursors; D011978:Receptors, Nicotinic; D038941:Polypyrimidine Tract-Binding Protein