The most common mutation for familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is in the chromosome 9 open reading frame 72 gene (C9ORF72). Identified in 2011, this mutation takes the form of a repeat expansion of the six nucleotides GGGGCC. Healthy people have up to 30 repeats; mutation carriers can have hundreds, but repeat sizing methods are only semi-quantitative and repeat length has not been linked to clinical features. The expansion also explains a portion of sporadic cases. It shows signs of genetic anticipation, leading to earlier onset in successive generations.
C9ORF72 expansions vary tremendously in their clinical expression between and among affected families, causing amnestic and psychiatric symptoms in addition to the established features of FTD and ALS. Regardless of their clinical phenotype, C9ORF72 cases all have widespread TDP-43 neuropathology in brain areas that show atrophy and correspond to symptoms. Separately, C9ORF72 cases also feature TDP-43-negative inclusions made of aggregation-prone dipeptide repeats. These dipeptides are translated from the hexanucleotide repeats—which reside in non-coding introns—in an unusual, bidirectional manner previously described for the neurodegenerative disease spinocerebellar ataxia type 8. Dipeptide inclusions appear in different cells than TDP-43 inclusions, and they do not track with neurodegeneration.
The pathogenic mechanisms underlying C9ORF72-associated ALS/FTD are under intense study. Hypotheses include a lack of functional gene product, toxicity of the repeat dipeptides, and sequestration of critical RNA-binding proteins in RNA foci. C9ORF72 encodes an uncharacterized protein whose normal function is not understood. Several lines of induced pluripotent stem cells from C9ORF72 patients have been established, as well as a zebrafish model. Further animal models of C9ORF72 are being developed.
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