NDLI: In Vitro Splicing Deficiency Induced by a C to T Mutation at Position −3 in the Intron 10 Acceptor Site of the Phenylalanine Hydroxylase Gene in a Patient with Phenylketonuria

Content Provider	Journal of Biological Chemistry (JBC)
Author	Jaruzelska, Jadwiga Abadie, Veronique D'Aubenton-Carafa, Yves Brody, Edward Munnich, Arnold Marie, Joëlle
Abstract	A previous study has identified a C → U mutation at position −3 in the 3′ splice site of intron 10 of the phenylalanine hydroxylase pre-mRNA in a patient with phenylketonuria. In vivo, this mutation induces the skipping of the downstream exon. This result is puzzling because both CAG and UAG have been reported to function equally as 3′ splice sites. In this report, we show that the C → U mutation affects predominantly the first step of the splicing reaction and that it blocks spliceosome assembly at an early stage. The 3′ region of the phenylalanine hydroxylase intron 10 has two unusual characteristic features: multiple potential branch sites and a series of four guanosine residues, which interrupt the polypyrimidine tract at positions −8 to −11 from the 3′ splice site. We show that the mutation precludes the use of the proximal branch site, while having no effect on the remote one. We also show that in the UAG transcript, the four guanosine residues inhibit the splicing of intron 10. The substitution of these purine residues by one cytosine residue, regardless of the position, increases the splicing efficiency of the mutant UAG precursor while having no effect on the wild-type CAG precursor. Substituting the four purine residues by four pyrimidines relieves the inhibition and rescues the use of the proximal branch site. These results demonstrate that according to the context, the C and U nucleotides preceding the AG are not equivalent for the splicing reaction.
Related Links	http://www.jbc.org/content/270/35/20370.abstract
Ending Page	20375
Starting Page	20370
Page Count	6
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	35
Volume Number	270
DOI	10.1074/jbc.270.35.20370
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1995-09-01
Access Restriction	Open
Subject Keyword	Nucleic Acids, Protein Synthesis, and Molecular Genetics
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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