title: CAG repeat expansion in autosomal dominant familial spastic paraparesis: novel expansion in a subset of patients.
abstract: Autosomal dominant familial spastic paraplegia (FSP) is a genetically heterogeneous neurodegenerative disorder displaying anticipation for which three loci have been mapped to the chromosomal positions 14q11.2-q24.3 (SPG3), 2p21-p24 (SPG4) and 15q11.1 (SPG6). The repeat expansion detection (RED) method has been used to demonstrate expanded CAG repeats in some FSP families that map to SPG4. We analyzed 20 FSP families, including four for which there is evidence for linkage to SPG4, and found that in most cases the repeat expansion detected by RED is due to non-pathogenic expansions of the chromosome 18q21.1 SEF2-1 or 17q21.3 ERDA1 locus. Polymorphic expansions at SEF2-1 and ERDA1 appear frequent and may confound RED studies in the search for genes causing disorders demonstrating anticipation. In six FSP families, however, CAG repeat expansion was detected in a subset of affected and at-risk individuals that did not result from expansion of the SEF2-1 and ERDA1 loci. Overall, 11 of 37 (30%) of the FSP patients with a CAG/CTG repeat expansion are unaccounted for by the SEF2-1 and ERDA1 loci, compared with two of 23 (9%) of the unaffected at-risk individuals and none of 19 controls. In the majority of cases these novel expansions were shorter than those previously reported.
authors.affiliation: Markey Molecular Medicine Center, Division of Medical Genetics and 6Division of General Internal Medicine, Department of Medicine, School of Medicine, University of Washington, 1705 NE Pacific Street, Box 357720, Seattle, WA 98195-7720, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Benson
authors.forename: M
authors.initials: M
authors.lastname: Horwitz
authors.forename: J
authors.initials: J
authors.lastname: Wolff
authors.forename: K
authors.initials: K
authors.lastname: Friend
authors.forename: E
authors.initials: E
authors.lastname: Thompson
authors.forename: S
authors.initials: S
authors.lastname: White
authors.forename: R I
authors.initials: RI
authors.lastname: Richards
authors.forename: W H
authors.initials: WH
authors.lastname: Raskind
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015153:Blotting, Western; D002886:Chromosomes, Human, Pair 17; D002887:Chromosomes, Human, Pair 18; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D035181:TATA-Box Binding Protein; 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 / Q000276:immunology / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D035181:TATA-Box Binding Protein; 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