Hexanucleotide repeat expansions in the C9ORF72 gene have been shown to be responsible for both familial and sporadic frontotemporal dementia/amyotrophic lateral sclerosis.
An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)<sub>30+</sub>) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9<sup>+</sup>).
Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
In this study, we have characterized both protein and RNA TDP-43 interactors from neuropathologically normal (control) and ALS-affected ventral lumbar spinal cord, including sporadic ALS (sALS) and familial cases harboring either a A4T mutant SOD1 or a 3' UTR *c.41G>A mutant FUS/TLS or expressing pathological c9orf72 expanded repeats.
Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay.
The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/motor neuron disease patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD.
Mutations in C9ORF72 and the genes encoding TDP-43 and FUS cause familial forms of FTD/ALS which provides evidence to link the pathology and genetics of these diseases.
FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS.
However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72.
Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide.
The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed.
The identification of mutations in transactive response DNA-binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease.
Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations.
Hexanucleotide repeat expansion in the bi-directionally transcribed C9orf72 gene is the most frequent cause of familial ALS and frontotemporal dementia (FTD).Kramer et al.
In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases.
We address neurodegeneration in repeat expansion disorders [Huntington's disease, spinocerebellar ataxias, C9ORF72-related amyotrophic lateral sclerosis (ALS)] and in diseases caused by deletions or point mutations (spinal muscular atrophy, most subtypes of familial ALS).
C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide.
The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9p21 has been discovered as the cause of approximately 20-50% of familial and up to 5-20% of sporadic amyotrophic lateral sclerosis (ALS) cases, making this the most common known genetic mutation of ALS to date.
Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey.
A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia.
An expanded hexanucleotide (GGGGCC) repeat in a non-coding promoter region of open reading frame 72 of chromosome 9 (C9ORF72) has been recently identified as a major cause of familial and sporadic frontotemporal lobar degeneration.