Isolation of CAG/CTG repeats from within the chromosome 2p21-p24 locus for autosomal dominant spastic paraplegia (SPG4) by YAC fragmentation

被引：1

作者：

J. Del-Favero

D. Goossens

P. De Jonghe

K. Benson

A. Michalik

D. Van den Bossche

M. Horwitz

C. Van Broeckhoven

机构：

[1] Department of Molecular Genetics,

[2] Flanders Interuniversity Institute for Biotechnology (VIB),undefined

[3] University of Antwerp (UIA),undefined

[4] Department of Biochemistry,undefined

[5] Antwerpen,undefined

[6] Belgium,undefined

[7] Division of Neurology,undefined

[8] University Hospital Antwerp (UZA),undefined

[9] Antwerpen,undefined

[10] Belgium,undefined

[11] Markey Molecular Medicine Center,undefined

[12] Division of Medical Genetics,undefined

[13] Department of Medicine,undefined

[14] School of Medicine,undefined

[15] University of Washington,undefined

[16] Seattle,undefined

[17] USA,undefined

[18] Contact address: J. Del-Favero,undefined

[19] Psychiatric Genetics Group,undefined

[20] University of Antwerp (UIA),undefined

[21] Department of Biochemistry,undefined

[22] Universiteitsplein 1,undefined

[23] B-2610 Antwerp,undefined

[24] Belgium,undefined

[25] e-mail: dfavero@uia.ua.ac.be,undefined

[26] Tel.: +32-38202332,undefined

[27] Fax: +32-38202541,undefined

来源：

Human Genetics | 1999年 / 105卷 / 3期

关键词：

Target Site; Homologous Recombination; Neurodegenerative Disorder; Paraplegia; Artificial Chromosome;

D O I：

10.1007/s004399900112

中图分类号：

学科分类号：

摘要：

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 (≥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.

引用

页码：217 / 225

页数：8

共 18 条

[1] Isolation of CAG/CTG repeat from within the chromosome 2p21-p24 locus for autosomal dominant spastic paraplegia (SPC4) by YAC fragmentation
Del-Favero, J
Goossens, D
De Jonghe, P
Benson, K
Michalik, A
Van den Bossche, D
Horwitz, M
Van Broeckhoven, C
HUMAN GENETICS, 1999, 105 (03) : 217 - 225
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Nielsen, JE
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Sorensen, SA
HUMAN MOLECULAR GENETICS, 1997, 6 (11) : 1811 - 1816
[3] A fine integrated map of the SPG4 locus excludes an expanded CAG repeat in chromosome 2p-linked autosomal dominant spastic paraplegia
Hazan, J
Davoine, CS
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GENOMICS, 1999, 60 (03) : 309 - 319
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JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 1998, 65 (05): : 693 - 696
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AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (04) : 372 - 372
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PERICAKVANCE, MA
LENNON, F
WASSERMAN, B
HENTATI, F
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CYTOGENETICS AND CELL GENETICS, 1994, 67 (04): : 244 - 244

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