title: A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.
abstract: 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.
authors.affiliation: George Browne Genetics Laboratory, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Breschel
authors.forename: M G
authors.initials: MG
authors.lastname: McInnis
authors.forename: R L
authors.initials: RL
authors.lastname: Margolis
authors.forename: G
authors.initials: G
authors.lastname: Sirugo
authors.forename: B
authors.initials: B
authors.lastname: Corneliussen
authors.forename: S G
authors.initials: SG
authors.lastname: Simpson
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: D F
authors.initials: DF
authors.lastname: MacKinnon
authors.forename: J F
authors.initials: JF
authors.lastname: Xu
authors.forename: N
authors.initials: N
authors.lastname: Pleasant
authors.forename: Y
authors.initials: Y
authors.lastname: Huo
authors.forename: R G
authors.initials: RG
authors.lastname: Ashworth
authors.forename: C
authors.initials: C
authors.lastname: Grundstrom
authors.forename: T
authors.initials: T
authors.lastname: Grundstrom
authors.forename: K K
authors.initials: KK
authors.lastname: Kidd
authors.forename: J R
authors.initials: JR
authors.lastname: DePaulo
authors.forename: C A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000483:Alleles; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001714:Bipolar Disorder / Q000235:genetics; D015139:Blotting, Southern; D002460:Cell Line; D002887:Chromosomes, Human, Pair 18; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017421:Sequence Analysis; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics*; D018911:Trinucleotide Repeats
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors