Disease-causing mutations in the gene were first discovered by two independent research teams, led by Rosa Rademakers of Mayo Clinic and Bryan Traynor of the National Institutes of Health, with their findings published in October 2011.

[6][7] The mutations in C9orf72 are significant because it is the first pathogenic mechanism identified to be a genetic link between familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).

[9] The gene was discovered in 2011 and is highly conserved in primates, other mammals and across different species: For example, it is nearly identical to humans in chimpanzee and rhesus macaque (99.58%), mouse (98.13%), rat (97.71%) and rabbit (98.54%), and Xenopus (83.96%), as well as zebrafish (75.97%).

The other is that the lack of the C9ORF72 protein due to interference of the expanded repeat to its transcription and splicing, (haploinsufficiency) causes the diseases.

[15][16][17] The GGGGCC repeat expansion in C9orf72 is also believed to compromise nucleocytoplasmic transport through several possible mechanisms.

[19] Numerous published studies have confirmed the commonality of the C9ORF72 repeat expansion in FTD and ALS, which are both diseases without cures that have affected millions of people.

[20] Amyotrophic lateral sclerosis is also devastating; it is characterized by motor neuron degeneration that eventually causes respiratory failure with a median survival of three years after onset.

Traditionally, familial and sporadic cases of ALS have been clinically indistinguishable, which has made diagnosis difficult.

The buildup of a repeat expansion with each generation is typically thought to occur because the DNA is unstable and therefore accumulates exponentially every time the gene is copied.

[22] Haplotype is a specific combination of multiple polymorphic sites along a chromosomal region that is inherited together in a block.

[11] Given the molecular role of known DENN modules,[31] the C9ORF72-like proteins were predicted to function as guanine nucleotide exchange factors (GEF), which activate small GTPases, most likely a Rab.

[10][32] This suggested that certain aspects of the ALS and FTD disease pathology might result from haploinsufficiency of C9ORF72, leading to a defect in intracellular membrane traffic, which adds to neuronal damage from RNA-mediated and dipeptide toxicities by reducing function of microglia, the macrophage-like cells of the brain.

[38] Repeat sequence expansion mutations in C9orf72 that lead to neurodegeneration in ALS/FTD display dysfunction of the nucleolus and of R-loop formation.

The C9orf72–SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen.

Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling, shedding light on a potential pathogenic mechanism related to the loss of C9orf72 function.

[40] Overall, the C9ORF72 mutation holds great promise for future therapies for familial FTD and/or ALS to be developed.