Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region ofC9ORF72Causes 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 geneC9ORF72that is strongly associated with diseas...

Full description

Saved in:
Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2011-10, Vol.72 (2), p.245
Main Authors: 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, Giovan ni, 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: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Chromosomes
Genes
Medical research
Mutation
Pathology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 geneC9ORF72that 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 theC9ORF72repeat 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 splicedC9ORF72transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion inC9ORF72is a major cause of both FTD and ALS.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2011.09.011