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

Abstract

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 non-coding 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 (22.5%). 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.

The phenotypic variability of amyotrophic lateral sclerosis

“…60 However, it was the discovery of a hexanucleotide expansion mutation in the C9orf72 gene-C9orf72 (GGGGCC)exp -that unequivocally linked the two ends of the spectrum. [61][62][63] This mutation underlies nearly half of cases of familial ALS and a quarter of cases of familial FTD. 1 The pathogenic mechanisms underpinning the connection between C9orf72 (GGGGCC)exp and ALS-FTD remain poorly understood, but the studies connecting the two have already changed our perceptions of these neuro degenerative disorders.…”

Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: Frequency of abnormality and effect on survival

“…The most prominent gene that causes ALS with cognitive impairment is C9orf72 [3,4], but there are others such as TARDBP and fused in sarcoma (FUS) [61,62].…”

“…Some people with ALS also have frontotemporal dementia (FTD) while others have lesser degrees of cognitive impairment [2]. Some of the overlap between ALS and FTD is associated with the presence of a C9orf72 gene mutation [3,4]. Different approaches have been used to study the frequency of cognitive impairment.…”

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…Up to 15% of patients with FTD concomitantly develop motor neuron disease (MND), and 10–20% of patients with MND develop FTD,3 suggesting that the two disorders lie on a clinical continuum. Pathogenic G 4 C 2 repeat expansions in chromosome 9 open reading frame 72 ( C9orf72) are the most common genetic cause of autosomal‐dominant FTD and amyotrophic lateral sclerosis (ALS) 4, 5. Potential pathomechanisms include the loss of function of normal C9orf72 protein, and/or toxicity resulting from the accumulation of G 4 C 2 transcripts that form RNA foci, interact with RNA‐binding proteins, and impair RNA processing 6.…”