共 55 条
Detection of Slipped-DNAs at the Trinucleotide Repeats of the Myotonic Dystrophy Type I Disease Locus in Patient Tissues
被引:51
作者:

Axford, Michelle M.
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Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Univ Toronto, Dept Mol Genet, Toronto, ON, Canada Hosp Sick Children, Toronto, ON M5G 1X8, Canada

Wang, Yuh-Hwa
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机构:
Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA Hosp Sick Children, Toronto, ON M5G 1X8, Canada

Nakamori, Masayuki
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机构:
Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA Hosp Sick Children, Toronto, ON M5G 1X8, Canada

Zannis-Hadjopoulos, Maria
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h-index: 0
机构:
McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada
McGill Univ, Dept Biochem, Montreal, PQ, Canada Hosp Sick Children, Toronto, ON M5G 1X8, Canada

Thornton, Charles A.
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h-index: 0
机构:
Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA Hosp Sick Children, Toronto, ON M5G 1X8, Canada

Pearson, Christopher E.
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h-index: 0
机构:
Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Univ Toronto, Dept Mol Genet, Toronto, ON, Canada Hosp Sick Children, Toronto, ON M5G 1X8, Canada
机构:
[1] Hosp Sick Children, Toronto, ON M5G 1X8, Canada
[2] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
[3] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA
[4] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA
[5] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada
[6] McGill Univ, Dept Biochem, Montreal, PQ, Canada
基金:
加拿大健康研究院;
关键词:
REPLICATION ORIGIN;
(CTG)CENTER-DOT(CAG) REPEATS;
HEXANUCLEOTIDE REPEAT;
COMPETITIVE PCR;
CAG REPEAT;
REPAIR;
BRAIN;
INSTABILITY;
EXPANSION;
GENE;
D O I:
10.1371/journal.pgen.1003866
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
Slipped-strand DNAs, formed by out-of-register mispairing of repeat units on complementary strands, were proposed over 55 years ago as transient intermediates in repeat length mutations, hypothesized to cause at least 40 neurodegenerative diseases. While slipped-DNAs have been characterized in vitro, evidence of slipped-DNAs at an endogenous locus in biologically relevant tissues, where instability varies widely, is lacking. Here, using an anti-DNA junction antibody and immunoprecipitation, we identify slipped-DNAs at the unstable trinucleotide repeats (CTG)n center dot(CAG)n of the myotonic dystrophy disease locus in patient brain, heart, muscle and other tissues, where the largest expansions arise in non-mitotic tissues such as cortex and heart, and are smallest in the cerebellum. Slipped-DNAs are shown to be present on the expanded allele and in chromatinized DNA. Slipped-DNAs are present as clusters of slip-outs along a DNA, with each slip-out having 1-100 extrahelical repeats. The allelic levels of slipped-DNA containing molecules were significantly greater in the heart over the cerebellum (relative to genomic equivalents of pre-IP input DNA) of a DM1 individual; an enrichment consistent with increased allelic levels of slipped-DNA structures in tissues having greater levels of CTG instability. Surprisingly, this supports the formation of slipped-DNAs as persistent mutation products of repeat instability, and not merely as transient mutagenic intermediates. These findings further our understanding of the processes of mutation and genetic variation.
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h-index: 0
机构:
Mayo Clin Rochester, Dept Neurol, Rochester, MN 55905 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Coppola, Giovanni
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Geschwind, Daniel H.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Wszolek, Zbigniew K.
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h-index: 0
机构:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Feldman, Howard
论文数: 0 引用数: 0
h-index: 0
机构:
Univ British Columbia, Div Neurol, Vancouver, BC V6T 2B5, Canada
Bristol Myers Squibb, Neurosci Global Clin Res, Wallingford, CT 06492 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Knopman, David S.
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h-index: 0
机构:
Mayo Clin Rochester, Dept Neurol, Rochester, MN 55905 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Petersen, Ronald C.
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h-index: 0
机构:
Mayo Clin Rochester, Dept Neurol, Rochester, MN 55905 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Miller, Bruce L.
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h-index: 0
机构:
Univ Calif San Francisco, Memory & Aging Ctr, Dept Neurol, San Francisco, CA 94143 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Dickson, Dennis W.
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h-index: 0
机构:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Boylan, Kevin B.
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h-index: 0
机构:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Graff-Radford, Neill R.
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h-index: 0
机构:
Mayo Clin Florida, Dept Neurol, Jacksonville, FL 32224 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada

Rademakers, Rosa
论文数: 0 引用数: 0
h-index: 0
机构:
Mayo Clin Florida, Dept Neurosci, Jacksonville, FL 32224 USA Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5C 1M9, Canada