Document Detail

Isolation of CAG/CTG repeats from within the chromosome 2p21-p24 locus for autosomal dominant spastic paraplegia (SPG4) by YAC fragmentation.
MedLine Citation:
PMID:  10987648     Owner:  NLM     Status:  MEDLINE    
Pure autosomal dominant spastic paraplegia (SPG) is a genetically heterogeneous neurodegenerative disorder of the central nervous system clinically characterized by progressive spasticity mainly affecting the lower limbs. Three distinct loci have been mapped to chromosomes 14q (SPG3), 2p (SPG4) and 15q (SPG6). In particular, SPG4 families show striking intrafamilial variability suggestive of anticipation and evidence has been provided that CAG/CTG repeat expansions may be involved. To isolate CAG/CTG repeat containing sequences from within the SPG4 candidate region, a novel approach was developed. Fragmentation vectors were assembled allowing direct fragmentation of yeast artificial chromosomes (YACs) with a short (> or = 21 bp) CAG/CTG sequence as the target site for homologous recombination. We used the CAG/CTG YAC fragmentation vectors to isolate CAG/CTG containing sequences from four YACs spanning the SPG4 candidate region between D2S400 and D2S367. A total of four CAG/CTG containing sequences were isolated of which three were novel. However, none of the four CAG/CTG repeats showed expanded alleles in two Belgian SPG4 families. In addition, we showed that the CAG/CTG alleles detected by the repeat expansion detection (RED) method could be fully explained by two polymorphic nonpathogenic CAG/CTG repeats on chromosomes 17 and 18, respectively. Also, the RED expansions in six SPG families could not be explained by amplification of the CAG/CTG repeats at the SPG4 locus. Together, our data do not support the hypothesis of a CAG/CTG repeat expansion as the molecular mechanism underlying SPG4 pathology.
J Del-Favero; D Goossens; P De Jonghe; K Benson; A Michalik; D Van den Bossche; M Horwitz; C Van Broeckhoven
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human genetics     Volume:  105     ISSN:  0340-6717     ISO Abbreviation:  Hum. Genet.     Publication Date:  1999 Sep 
Date Detail:
Created Date:  2000-09-18     Completed Date:  2000-09-18     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7613873     Medline TA:  Hum Genet     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  217-25     Citation Subset:  IM    
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerpen, Belgium.
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MeSH Terms
Adenosine Triphosphatases / genetics*
Chromosomes, Artificial, Yeast / genetics
Chromosomes, Human, Pair 2 / genetics*
DNA / chemistry,  genetics,  isolation & purification
DNA Fragmentation
Electrophoresis, Gel, Pulsed-Field
Family Health
Sequence Analysis, DNA
Spastic Paraplegia, Hereditary / genetics*
Trinucleotide Repeat Expansion / genetics
Trinucleotide Repeats / genetics*
Reg. No./Substance:
9007-49-2/DNA; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/SPAST protein, human

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