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Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with dise... Full description

Journal Title: Neuron 2011, Vol.72 (2), p.245-256
Main Author: DeJesus-Hernandez, Mariely
Other Authors: Mackenzie, Ian R , Boeve, Bradley F , Boxer, Adam L , Baker, Matt , Rutherford, Nicola J , Nicholson, Alexandra M , Finch, NiCole A , Flynn, Heather , Adamson, Jennifer , Kouri, Naomi , Wojtas, Aleksandra , Sengdy, Pheth , Hsiung, Ging-Yuek R , Karydas, Anna , Seeley, William W , Josephs, Keith A , Coppola, Giovanni , Geschwind, Daniel H , Wszolek, Zbigniew K , Feldman, Howard , Knopman, David S , Petersen, Ronald C , Miller, Bruce L , Dickson, Dennis W , Boylan, Kevin B , Graff-Radford, Neill R , Rademakers, Rosa
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/21944778
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title: Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
format: Article
creator:
  • DeJesus-Hernandez, Mariely
  • Mackenzie, Ian R
  • Boeve, Bradley F
  • Boxer, Adam L
  • Baker, Matt
  • Rutherford, Nicola J
  • Nicholson, Alexandra M
  • Finch, NiCole A
  • Flynn, Heather
  • Adamson, Jennifer
  • Kouri, Naomi
  • Wojtas, Aleksandra
  • Sengdy, Pheth
  • Hsiung, Ging-Yuek R
  • Karydas, Anna
  • Seeley, William W
  • Josephs, Keith A
  • Coppola, Giovanni
  • Geschwind, Daniel H
  • Wszolek, Zbigniew K
  • Feldman, Howard
  • Knopman, David S
  • Petersen, Ronald C
  • Miller, Bruce L
  • Dickson, Dennis W
  • Boylan, Kevin B
  • Graff-Radford, Neill R
  • Rademakers, Rosa
subjects:
  • Alleles
  • Amyotrophic lateral sclerosis
  • Amyotrophic Lateral Sclerosis - genetics
  • Analysis
  • C9orf72 Protein
  • Chromosomes, Human, Pair 9
  • Cytogenetics
  • Dementia
  • DNA Repeat Expansion
  • Female
  • Frontotemporal Dementia - genetics
  • Genes
  • Genetic disorders
  • Genetic Predisposition to Disease
  • Genetic research
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Medical colleges
  • Microsatellite Repeats
  • Neurons
  • Neuroscience(all)
  • Neurosciences
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Proteins - genetics
  • RNA
ispartof: Neuron, 2011, Vol.72 (2), p.245-256
description: Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. ► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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titleExpanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
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creatorDeJesus-Hernandez, Mariely ; Mackenzie, Ian R ; Boeve, Bradley F ; Boxer, Adam L ; Baker, Matt ; Rutherford, Nicola J ; Nicholson, Alexandra M ; Finch, NiCole A ; Flynn, Heather ; Adamson, Jennifer ; Kouri, Naomi ; Wojtas, Aleksandra ; Sengdy, Pheth ; Hsiung, Ging-Yuek R ; Karydas, Anna ; Seeley, William W ; Josephs, Keith A ; Coppola, Giovanni ; Geschwind, Daniel H ; Wszolek, Zbigniew K ; Feldman, Howard ; Knopman, David S ; Petersen, Ronald C ; Miller, Bruce L ; Dickson, Dennis W ; Boylan, Kevin B ; Graff-Radford, Neill R ; Rademakers, Rosa
creatorcontribDeJesus-Hernandez, Mariely ; Mackenzie, Ian R ; Boeve, Bradley F ; Boxer, Adam L ; Baker, Matt ; Rutherford, Nicola J ; Nicholson, Alexandra M ; Finch, NiCole A ; Flynn, Heather ; Adamson, Jennifer ; Kouri, Naomi ; Wojtas, Aleksandra ; Sengdy, Pheth ; Hsiung, Ging-Yuek R ; Karydas, Anna ; Seeley, William W ; Josephs, Keith A ; Coppola, Giovanni ; Geschwind, Daniel H ; Wszolek, Zbigniew K ; Feldman, Howard ; Knopman, David S ; Petersen, Ronald C ; Miller, Bruce L ; Dickson, Dennis W ; Boylan, Kevin B ; Graff-Radford, Neill R ; Rademakers, Rosa
descriptionSeveral families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. ► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
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languageeng
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subjectAlleles ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; Analysis ; C9orf72 Protein ; Chromosomes, Human, Pair 9 ; Cytogenetics ; Dementia ; DNA Repeat Expansion ; Female ; Frontotemporal Dementia - genetics ; Genes ; Genetic disorders ; Genetic Predisposition to Disease ; Genetic research ; Genotype ; Haplotypes ; Humans ; Male ; Medical colleges ; Microsatellite Repeats ; Neurons ; Neuroscience(all) ; Neurosciences ; Pedigree ; Polymorphism, Single Nucleotide ; Proteins - genetics ; RNA
ispartofNeuron, 2011, Vol.72 (2), p.245-256
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1Mackenzie, Ian R
2Boeve, Bradley F
3Boxer, Adam L
4Baker, Matt
5Rutherford, Nicola J
6Nicholson, Alexandra M
7Finch, NiCole A
8Flynn, Heather
9Adamson, Jennifer
10Kouri, Naomi
11Wojtas, Aleksandra
12Sengdy, Pheth
13Hsiung, Ging-Yuek R
14Karydas, Anna
15Seeley, William W
16Josephs, Keith A
17Coppola, Giovanni
18Geschwind, Daniel H
19Wszolek, Zbigniew K
20Feldman, Howard
21Knopman, David S
22Petersen, Ronald C
23Miller, Bruce L
24Dickson, Dennis W
25Boylan, Kevin B
26Graff-Radford, Neill R
27Rademakers, Rosa
title
0Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
1Neuron
addtitleNeuron
descriptionSeveral families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. ► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
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1Amyotrophic lateral sclerosis
2Amyotrophic Lateral Sclerosis - genetics
3Analysis
4C9orf72 Protein
5Chromosomes, Human, Pair 9
6Cytogenetics
7Dementia
8DNA Repeat Expansion
9Female
10Frontotemporal Dementia - genetics
11Genes
12Genetic disorders
13Genetic Predisposition to Disease
14Genetic research
15Genotype
16Haplotypes
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18Male
19Medical colleges
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21Neurons
22Neuroscience(all)
23Neurosciences
24Pedigree
25Polymorphism, Single Nucleotide
26Proteins - genetics
27RNA
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1Mackenzie, Ian R
2Boeve, Bradley F
3Boxer, Adam L
4Baker, Matt
5Rutherford, Nicola J
6Nicholson, Alexandra M
7Finch, NiCole A
8Flynn, Heather
9Adamson, Jennifer
10Kouri, Naomi
11Wojtas, Aleksandra
12Sengdy, Pheth
13Hsiung, Ging-Yuek R
14Karydas, Anna
15Seeley, William W
16Josephs, Keith A
17Coppola, Giovanni
18Geschwind, Daniel H
19Wszolek, Zbigniew K
20Feldman, Howard
21Knopman, David S
22Petersen, Ronald C
23Miller, Bruce L
24Dickson, Dennis W
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titleExpanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
authorDeJesus-Hernandez, Mariely ; Mackenzie, Ian R ; Boeve, Bradley F ; Boxer, Adam L ; Baker, Matt ; Rutherford, Nicola J ; Nicholson, Alexandra M ; Finch, NiCole A ; Flynn, Heather ; Adamson, Jennifer ; Kouri, Naomi ; Wojtas, Aleksandra ; Sengdy, Pheth ; Hsiung, Ging-Yuek R ; Karydas, Anna ; Seeley, William W ; Josephs, Keith A ; Coppola, Giovanni ; Geschwind, Daniel H ; Wszolek, Zbigniew K ; Feldman, Howard ; Knopman, David S ; Petersen, Ronald C ; Miller, Bruce L ; Dickson, Dennis W ; Boylan, Kevin B ; Graff-Radford, Neill R ; Rademakers, Rosa
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0Alleles
1Amyotrophic lateral sclerosis
2Amyotrophic Lateral Sclerosis - genetics
3Analysis
4C9orf72 Protein
5Chromosomes, Human, Pair 9
6Cytogenetics
7Dementia
8DNA Repeat Expansion
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13Genetic Predisposition to Disease
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19Medical colleges
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21Neurons
22Neuroscience(all)
23Neurosciences
24Pedigree
25Polymorphism, Single Nucleotide
26Proteins - genetics
27RNA
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6Nicholson, Alexandra M
7Finch, NiCole A
8Flynn, Heather
9Adamson, Jennifer
10Kouri, Naomi
11Wojtas, Aleksandra
12Sengdy, Pheth
13Hsiung, Ging-Yuek R
14Karydas, Anna
15Seeley, William W
16Josephs, Keith A
17Coppola, Giovanni
18Geschwind, Daniel H
19Wszolek, Zbigniew K
20Feldman, Howard
21Knopman, David S
22Petersen, Ronald C
23Miller, Bruce L
24Dickson, Dennis W
25Boylan, Kevin B
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7Finch, NiCole A
8Flynn, Heather
9Adamson, Jennifer
10Kouri, Naomi
11Wojtas, Aleksandra
12Sengdy, Pheth
13Hsiung, Ging-Yuek R
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15Seeley, William W
16Josephs, Keith A
17Coppola, Giovanni
18Geschwind, Daniel H
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21Knopman, David S
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jtitleNeuron
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date2011-10-20
risdate2011
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issue2
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issn0896-6273
eissn1097-4199
abstractSeveral families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. ► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
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pmid21944778
doi10.1016/j.neuron.2011.09.011
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