Human Molecular Genetics, Vol 6, 1855-1863, Copyright © 1997 by Oxford University Press
TS Breschel, MG McInnis, RL Margolis, G Sirugo, B Corneliussen, SG Simpson, FJ McMahon, DF MacKinnon, JF Xu, N Pleasant, Y Huo, RG Ashworth, C Grundstrom, T Grundstrom, KK Kidd, JR DePaulo and CA Ross
There are currently 13 diseases known to be caused by unstable triplet
repeat mutations; however, there are some instances (as with FRAXF and
FRA16) when these mutations appear to be asymptomatic. In a search for
polymorphic CTG repeats as candidate genes for bipolar disorder, we
screened a genomic human chromosome 18-specific library and identified a
1.6 kb clone (7,6A) with a CTG24 repeat that maps to 18q21.1. The CTG
repeat locus, termed CTG18.1, is located within an intron of human SEF2- 1,
a gene encoding a basic hellx-loop-hellx DNA binding protein involved in
transcriptional regulation. The CTGn repeat is highly polymorphic and very
enlarged alleles, consistent with expansions of up to CTG2100, were
identified. PCR and Southern blot analysis in pedigrees ascertained for a
Johns Hopkins University bipolar disorder linkage study and in CEPH
reference pedigrees revealed a tripartite distribution of CTG18.1 alleles
with stable alleles (CTG10-CTG37), moderately enlarged and unstable alleles
(CTG53-CTG250), and very enlarged, unstable alleles (CTG800-CTG2100).
Moderately enlarged alleles were not associated with an abnormal phenotype
and have a combined enlarged allele frequency of 3% in the CEPH and bipolar
populations. Very enlarged alleles, detectable only by Southern blot
analysis of genomic digests, have thus far been found in only three
individuals from our bipolar pedigrees, and to date, have not been found in
any of the CEPH reference pedigrees. These enlarged alleles may arise, at
least in part, via somatic mutation.
ARTICLES
A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1
George Browne Genetics Laboratory, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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