MUTATIONS THAT ALTER RNA SPLICING OF THE HUMAN HPRT GENE - A REVIEW OF THE SPECTRUM

Citation
Jp. Oneil et al., MUTATIONS THAT ALTER RNA SPLICING OF THE HUMAN HPRT GENE - A REVIEW OF THE SPECTRUM, Mutation research. Reviews in mutation research, 411(3), 1998, pp. 179-214
Citations number
130
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Genetics & Heredity",Toxicology,"Biothechnology & Applied Migrobiology
ISSN journal
1383-5742
Volume
411
Issue
3
Year of publication
1998
Pages
179 - 214
Database
ISI
SICI code
1383-5742(1998)411:3<179:MTARSO>2.0.ZU;2-G
Abstract
The human HPRT gene contains spans approximately 42,000 base pairs in genomic DNA, has a mRNA of approximately 900 bases and a protein codin g sequence of 657 bases (initiation codon AUG to termination codon UAA ). This coding sequence is distributed into 9 exons ranging from 18 (e xon 5) to 184 (exon 3) base pairs. Intron sizes range from 170 (intron 7) to 13,075 (intron 1) base pairs. In a database of human HPRT mutat ions, 277 of 2224 (12.5%) mutations result in alterations in splicing of the mRNA as analyzed by both reverse transcriptase mediated product ion of a cDNA followed by PCR amplification and cDNA sequencing and by genomic DNA PCR amplification and sequencing. Mutations have been fou nd in all eight 5' (donor) and 3' (acceptor) splice sequences. Mutatio ns in the 5' splice sequences of introns 1 and 5 result in intron incl usion in the cDNA due to the use of cryptic donor splice sequences wit hin the introns; mutations in the other six 5' sites result in simple exon exclusion. Mutations in the 3' splice sequences of introns 1, 3, 7 and 8 result in partial exon exclusion due to the use of cryptic acc eptor splice sequences within the exons; mutations in the other four 3 ' sites result in simple exon exclusion. A base substitution in exon 3 (209G --> T) creates a new 5' (donor) splice site which results in th e exclusion of 110 bases of exon 3 from the cDNA. Two base substitutio ns in intron 8 (IVS8-16G --> A and IVS8-3T --> G) result in the inclus ion of intron 8 sequences in the cDNA due to the creation of new 3' (a cceptor) splice sites. Base substitution within exons 1, 3, 4, 6 and 8 also result in splice alterations in cDNA. Those in exons 1 and 6 are at the 3' end of the exon and may directly affect splicing. Those wit hin exons 3 and 4 may be the result of the creation of nonsense codons , while those in exon 8 cannot be explained by this mechanism. Lastly, many mutations that affect splicing of the HPRT mRNA have pleiotropic effects in that multiple cDNA products are found. (C) 1998 Elsevier S cience B.V. All rights reserved.