NDLI: Site-specific base changes in the coding or promoter region of the human β- and γ-globin genes by single-stranded oligonucleotides

Content Provider	PubMed Central
Author	Yin, Wenxuan Kren, Betsy T. Steer, Clifford J.
Copyright Year	2005
Abstract	SSOs (single-stranded oligonucleotides) can mediate site-specific alteration of base-pairs in episomal and chromosomal target genes in mammalian cells. The TNE (targeted nucleotide exchange) can result in either repair or mutation of a gene sequence and is mediated through endogenous DNA repair pathway(s). Thus the approach provides a technique for the treatment of monogenic disorders associated with specific point mutations such as SCD (sickle cell disease). We studied the potential application of SSOs for SCD by introducing either an A to T substitution at the sixth codon of the human β-globin gene (sickle locus) or a C to G mutation at −202 of the Gγ-globin gene promoter region. The latter TNE is an alternative strategy to ameliorate the clinical manifestations of sickle cell anaemia by re-activating fetal haemoglobin gene expression in adult erythrocytes. A sensitive and valid PCR assay system was developed, which allows detection of point mutations as low as 0.01% at these sites. Using this system, TNE between 0.01 and 0.1% at the sickle locus or γ-globin gene promoter region was detected after transfection with SSOs in cultured human cell lines. TNE in the Gγ-globin promoter region exhibited varying degrees of strand bias that was dependent on SSO design and the cell's DNA mismatch repair activity. The results suggest that the endogenous DNA repair machinery may permit SSO correction of the sickle defect by modification of the β- and/or γ-globin genes.
Related Links	http://dx.doi.org/10.1042/bj20050045
Ending Page	261
Page Count	9
Starting Page	253
File Format	PDF
ISSN	02646021
e-ISSN	14708728
Journal	Biochemical Journal
Issue Number	Pt 1
Volume Number	390
Language	English
Publisher	Portland Press Ltd.
Publisher Date	2005-08-15
Access Restriction	Open
Rights Holder	Portland Press Ltd.
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry

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