title: The spfash mouse: a missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing.
abstract: Ornithine transcarbamylase (ornithine carbamoyltransferase; carbamoyl-phosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3) is a mitochondrial matrix enzyme of the mammalian urea cycle. The X chromosome-linked spfash mutation in the mouse causes partial ornithine transcarbamylase deficiency and has served as a model for the human disease. We show here that the spfash mutation is a guanine to adenine transition of the last nucleotide of the fourth exon of the ornithine transcarbamylase gene. This nucleotide change produces two remarkably different effects. First, this transition causes ornithine transcarbamylase mRNA deficiency because the involved exon nucleotide plays a part in the recognition of the adjacent splice donor site. As a result of the mutation, ornithine transcarbamylase pre-mRNA is spliced inefficiently both at this site and at a cryptic splice donor site 48 bases into the adjacent intron. Second, two mutant proteins are translated from these mRNAs. From the correctly spliced mRNA, the transition results in a change of amino acid 129 from arginine to histidine. This missense substitution has no discernable effect on mitochondrial import, subunit assembly, or enzyme activity. On the other hand, the elongated mRNA resulting from mis-splicing is translated into a dysfunctional ornithine transcarbamylase subunit elongated by the insertion of 16 amino acid residues.
authors: Yale University School of Medicine, Department of Human Genetics, New Haven, CT 06510.
authors: P E
authors: PE
authors: Hodges
authors: L E
authors: LE
authors: Rosenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004259:DNA-Directed DNA Polymerase; D004720:Endonucleases; D005784:Gene Amplification; D005796:Genes; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D009954:Ornithine Carbamoyltransferase / Q000235:genetics*; D012313:RNA / Q000235:genetics; D012326:RNA Splicing; D016372:RNA, Antisense; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics*; D015719:Single-Strand Specific DNA and RNA Endonucleases
chemical_list: D003062:Codon; D016372:RNA, Antisense; D012333:RNA, Messenger; D012313:RNA; D004247:DNA; D009954:Ornithine Carbamoyltransferase; D004259:DNA-Directed DNA Polymerase; D004720:Endonucleases; D015719:Single-Strand Specific DNA and RNA Endonucleases