title: Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect.
abstract: Approximately 2% of Caucasians and African-Americans are homozygous for a nonsense mutation in exon 2 of the AMPD1 (AMP deaminase) gene. These individuals have a high grade deficiency of AMPD activity in their skeletal muscle. More than 100 patients with AMPD1 deficiency have been reported to have symptoms of a metabolic myopathy, but it is apparent many individuals with this inherited defect are asymptomatic given the prevalence of this mutant. Results of the present study provide a potential molecular explanation for "correction" of this genetic defect. Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle. Expression studies document that AMPD1 mRNA, which has exon 2 deleted, encodes a functional AMPD peptide. A much higher percentage of alternatively spliced transcripts are found during differentiation of human myocytes in vitro. Transfection studies with human minigene constructs demonstrate that alternative splicing of the primary transcript of human AMPD1 is controlled by tissue-specific and stage-specific signals. Alternative splicing of exon 2 in individuals who have inherited this defect provides a mechanism for phenotypic rescue and variations in splicing patterns may contribute to the variability in clinical symptoms.
authors: Seymour Gray Molecular Medicine Laboratory, Department of Medicine, University of Pennsylvania, Philadelphia 19104-4283.
authors: H
authors: H
authors: Morisaki
authors: T
authors: T
authors: Morisaki
authors: L K
authors: LK
authors: Newby
authors: E W
authors: EW
authors: Holmes
mesh_terms: D000659:AMP Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000235:genetics; D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D005091:Exons; D005796:Genes; D006720:Homozygote; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology*; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014162:Transfection; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D000199:Actins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000659:AMP Deaminase; C577245:AMPD1 protein, mouse