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PMID: 9580685 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cloned human FMR1 trinucleotide repeats exhibit a length- and orientation-dependent instability suggestive of in vivo lagging strand secondary structure.

Nucleic acids research ·Vol. 26 ·No. 10 ·1998-05-15 ·Pages 2353-8

Hirst MC, White PJ

Abstract

The normal human FMR1 gene contains a genetically stable (CGG) n trinucleotide repeat which usually carries interspersed AGG triplets. An increase in repeat number and the loss of interspersions results in array instability, predominantly expansion, leading to FMR1 gene silencing. Instability is directly related to the length of the uninterrupted (CGG) n repeat and is widely assumed to be related to an increased propensity to form G-rich secondary structures which lead to expansion through replication slippage. In order to investigate this we have cloned human FMR1 arrays with internal structures representing the normal, intermediate and unstable states. In one replicative orientation, arrays show a length-dependent instability, deletions occurring in a polar manner. With longer arrays these extend into the FMR1 5'-flanking DNA, terminating at either of two short CGG triplet arrays. The orientation-dependent instability suggests that secondary structure forms in the G-rich lagging strand template, resolution of which results in intra-array deletion. These data provide direct in vivo evidence for a G-rich lagging strand secondary structure which is believed to be involved in the process of triplet expansion in humans.

MeSH Terms
Cloning, Molecular DNA/chemistry,genetics DNA Replication/genetics Escherichia coli/genetics Fragile X Mental Retardation Protein Fragile X Syndrome/genetics Humans Models, Genetic Nerve Tissue Proteins/genetics Nucleic Acid Conformation RNA-Binding Proteins Sequence Analysis, DNA Sequence Deletion Trinucleotide Repeats
Chemicals
FMR1 protein, human Nerve Tissue Proteins RNA-Binding Proteins Fragile X Mental Retardation Protein DNA
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Hirst M C
Institute of Molecular Medicine, The John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DS, UK. mhirst@worf.molbiol.ox.ac.uk
White P J
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
0305-1048
DOI
10.1093/nar/26.10.2353
Email
mhirst@worf.molbiol.ox.ac.uk
Published
1998-05-15
Pages
2353-8
Language
English
Region
England
NLM ID
0411011
PMCID
PMC147547
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1093/nar/26.10.2353 PMC Full Text View journal details
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