TY - JOUR
T1 - Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
AU - DeJesus-Hernandez, Mariely
AU - Mackenzie, Ian R.
AU - Boeve, Bradley F.
AU - Boxer, Adam L.
AU - Baker, Matt
AU - Rutherford, Nicola J.
AU - Nicholson, Alexandra M.
AU - Finch, Ni Cole A.
AU - Flynn, Heather
AU - Adamson, Jennifer
AU - Kouri, Naomi
AU - Wojtas, Aleksandra
AU - Sengdy, Pheth
AU - Hsiung, Ging Yuek R.
AU - Karydas, Anna
AU - Seeley, William W.
AU - Josephs, Keith A.
AU - Coppola, Giovanni
AU - Geschwind, Daniel H.
AU - Wszolek, Zbigniew K.
AU - Feldman, Howard
AU - Knopman, David S.
AU - Petersen, Ronald C.
AU - Miller, Bruce L.
AU - Dickson, Dennis W.
AU - Boylan, Kevin B.
AU - Graff-Radford, Neill R.
AU - Rademakers, Rosa
N1 - Funding Information:
We are grateful to all patients, family members, and caregivers who participated in this study. The expert technical assistance of Pamela Desaro, Amelia Johnston, and Thomas Kryston in the collection of DNA and postmortem tissue in the Mayo Clinic Florida ALS Center and of Margaret Luk in performing immunohistochemistry at UBC is also acknowledged. We also thank Richard Crook, Jennifer Gass, and Ashley Cannon for technical assistance with the genetic and expression analyses. This research was funded as part of the Mayo Clinic ADRC grant from the National Institute on Aging (P50 AG016574), and members of one family were participants in the Mayo Clinic Alzheimer's Disease Patient Registry (ADPR) from the National Institute on Aging (U01 AG006786). Research was further funded by the ALS Association (R.R.), Mayo Foundation and MCF ALS Center donor funds (K.B.B.). R.R. is also funded by NIH grants R01 NS065782 and R01 AG026251. Some TDP-43 analysis was funded by NIH grant R01 AG037491 (K.A.J.). Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052).The UBC studies were funded by the Canadian Institutes of Health Research (CIHR) Operating Grants #179009 and #74580 and by the Pacific Alzheimer's Research Foundation (PARF) Center Grant C06-01. G-YRH is supported by a Clinical Genetics Investigatorship award from the CIHR. A.L.B. is funded by R01AG038791, R01AG031278, the John Douglas French Foundation, the Hellman Family Foundation, and the Tau Research Consortium. B.L.M. is funded by P50AG023501, P01AG019724, the Larry Hillblom Foundation, and the State of CA and P50 AG1657303 to B.L.M. and W.W.S.
PY - 2011/10/20
Y1 - 2011/10/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80054832080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80054832080&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2011.09.011
DO - 10.1016/j.neuron.2011.09.011
M3 - Article
C2 - 21944778
AN - SCOPUS:80054832080
SN - 0896-6273
VL - 72
SP - 245
EP - 256
JO - Neuron
JF - Neuron
IS - 2
ER -