C9ORF72 hexanucleotide expansions of 20–22 repeats are associated with frontotemporal deterioration

Abstract

Description of these families suggests that short C9ORF72 hexanucleotide expansions are also related to frontotemporal cognitive deterioration.

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

“…It is also found in nearly 10 and 5% of patients with apparent nonfamilial ALS or FTD, respectively [37]. Control individuals most often carry 2-8 repeats, whereas patients have hundreds and even up to several thousands of repeats [46,24]. At the cellular level, ALS/FTD associated with the C9orf72 expansion mutation (here called C9 ALS/FTD) is characterised by nuclear, and to a lesser extent cytoplasmic, RNA foci that contain sense GGG GCC or antisense CCC CGG repeats [26].…”

C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles

“…We and others have shown that the majority of C9ORF72 neurodegeneration patients carry a repeat expansion of .2,000 repeats, 5 although it has been suggested that more than 30 1,2 or even as little as 20 to 22 repeats in 1 C9ORF72 allele are pathogenic. 7 A recent study has reported hypermethylation of a CpG island 59 to the repeat sequence, which did not occur in samples with intermediate-length expansions of up to 43 repeats. 8 If this is the mechanism underlying reduced mRNA expression, then it should not affect smaller repeat sizes.…”

The Disease-associated r(GGGGCC) Repeat from the C9orf72 Gene Forms Tract Length-dependent Uni- and Multimolecular RNA G-quadruplex Structures

“…It was recently reported that an expansion of a (GGGGCC) n ⅐(GGCCCC) n repeat within a noncoding region of C9orf72 could cause ALS and FTD (3,4). Unaffected individuals have 2-19 repeats, whereas affected individuals have 250 -1600 repeats and can show symptoms with as few as 20 -22 repeats (5). The C9orf72 transcript with the expanded repeat was shown to aberrantly aggregate into RNA nuclear foci (4).…”