Human Molecular Genetics, Vol 7, 1935-1946, Copyright © 1998 by Oxford University Press
C Gunter, W Paradee, DC Crawford, KA Meadows, J Newman, CB Kunst, DL Nelson, C Schwartz, A Murray, JN Macpherson, SL Sherman and ST Warren
In at least 98% of fragile X syndrome cases, the disease results from
expansion of the CGG repeat in the 5' end of FMR1. The use of
microsatellite markers in the FMR1 region has revealed a disparity of risk
between haplotypes for CGG repeat expansion. Although instability appears
to depend on both the haplotype and the AGG interspersion pattern of the
repeat, these factors alone do not completely describe the molecular basis
for the linkage disequilibrium between normal and fragile X chromosomes, in
part due to instability of the marker loci themselves. In an effort to
better understand the mechanism of dynamic mutagenesis, we have searched
for and discovered a single nucleotide polymorphism in intron 1 of FMR1 and
characterized this marker, called ATL1, in 564 normal and 152 fragile X
chromosomes. The G allele of this marker is found in 40% of normal
chromosomes, in contrast to 83% of fragile X chromosomes. Not only is the G
allele exclusively linked to haplotypes over-represented in fragile X
syndrome, but G allele chromosomes also appear to transition to instability
at a higher rate on haplotypes negatively associated with risk of
expansion. The two alleles of ATL1 also reveal a highly significant linkage
disequilibrium between unstable chromosomes and the 5' end of the CGG
repeat itself, specifically the position of the first AGG interruption. The
data expand the number of haplotypes associated with FMR1 and specifically
allow discrimination, by ATL1 alleles, of single haplotypes with differing
predispositions to expansion. Such haplotypes should prove useful in
further defining the mechanism of dynamic mutagenesis.
ARTICLES
Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1
Departments of Biochemistry, Pediatrics and Genetics, Emory University School of Medicine and Howard Hughes Medical Institute, Emory University, Atlanta, GA 30322, USA.
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