title: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: NiCole A
authors.initials: NA
authors.lastname: Finch
authors.forename: Heather
authors.initials: H
authors.lastname: Flynn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Naomi
authors.initials: N
authors.lastname: Kouri
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.forename: Pheth
authors.initials: P
authors.lastname: Sengdy
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D002899:Chromosomes, Human, Pair 9; D042622:DNA Repeat Expansion; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins