C9orf72

Cytogenetic Location: 9p21.2

Molecular Location on chromosome 9: base pairs 27,546,546 to 27,573,866

The C9orf72 gene is located on the short (p) arm of chromosome 9 at position 21.2.

More precisely, the C9orf72 gene is located from base pair 27,546,546 to base pair 27,573,866 on chromosome 9.

The mutation of C9ORF72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC.[9] In a person without the mutation, there are few repeats of this hexanucleotide, typically less than 20–30,[10] but in people with the mutation, the repeat can occur in the order of hundreds.[11] It is known that the mutation interferes with normal expression of the protein made by C9orf72, however the function of this protein remains speculative. There are two major theories about the way that the C9ORF72 mutation causes FTD and/or ALS. One theory is that accumulation of RNA in the nucleus and cytoplasm becomes toxic, and RNA binding protein sequestration occurs. The other is that the lack of half of the C9ORF72 protein (Haploinsufficiency) in the body causes the diseases. Additionally, RNA transcribed from the C9ORF72 gene, containing expanded GGGGCC repeats, is translated through a non-ATG initiated mechanism, which is the same mechanism as other repeat disorders. This hexanucleotide varant of a trinucleotide repeat disorder produces five different dipeptides by RAN translation, these dipeptides aggregating to contribute to overall toxicity of the mutation.[12][13][14] The GGGGCC repeat expansion in C9orf72 is also believed to compromise nucleocytoplasmic transport through several possible mechanisms.[15]

The C9ORF72 mutation is the first mutation found to be a link between familial FTD and ALS.[16] 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. Frontotemporal dementia is the second most common form of early-onset dementia after Alzheimer's disease in people under the age of 65.[17] 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.[18]

C9orf72 is present in approximately 40% of familial ALS and 8-10 % of sporadic ALS. It is currently the most common demonstrated mutation related to ALS - far more common than SOD1 or TDP-43.

While different mutations of various genes have been linked to different phenotypes of FTD in the past, C9orf72 specifically has been linked to behavioral variant FTD.[19] Certain pathology in FTD caused by the C9orf72 mutation can also include:

• TDP-43 in all C9 carriers[20]
• Ubiquitin-binding protein 62[21]

C9ORF72 is specifically linked to familial ALS, which affects about 10% of ALS patients. Traditionally, familial and sporadic cases of ALS have been clinically indistinguishable, which has made diagnosis difficult. The identification of this gene will therefore help in the future diagnosis of familial ALS.[18] Slow diagnosis is also common for FTD, which can often take up to a year with many patients initially misdiagnosed with another condition. Testing for a specific gene that is known to cause the diseases would help with faster diagnoses. Possibly most importantly, the identification of this hexanucleotide repeat expansion is an extremely promising avenue for possible future therapies of both familial FTD and familial ALS, once the mechanism and function of the C9ORF72 protein is better comprehended. Furthermore, present research is being done to see if there is a correlation between C9ORF72 and other neurological diseases, such as motor neuron disease and Huntington's disease.[22][23]

It is possible that genetic anticipation may exist for this mutation. However, only 1 in 4 families exhibited significant anticipation in this study (n=63) [20] It has been proposed that the amount of the repeat expansion increases with each successive generation, possibly causing the disease to be more severe in the next generation, showing onset up to a decade earlier with each successive generation after the carrier. 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. No genetic evidence for this has yet been demonstrated for this mutation.[16] There is also a demographic factor that should be considered in genetic predisposition, as some cohorts have found that there might be a founder effect for the C9orf72 mutation, which might have led to higher frequencies of the mutation in specific populations than others. Specifically this founder has been linked to Northern Europeans populations, namely Finland.[19]

C9ORF72 is predicted to be a full-length homologue of DENN proteins (where DENN stands for "differentially expressed in normal and neoplastic cells").[26][27][28] These proteins have a conserved DENN module consisting of an N-terminal longin domain, followed by the central DENN and C-terminal alpha-helical d-DENN domains.[27] This led to DENNL72 being suggested as a new name for C9orf72.[28]

Given the molecular role of known DENN modules,[29] the C9ORF72-like proteins were predicted to function as Guanine nucleotide exchange factors (GEF), which activate small GTPases, most likely a Rab. Studies have provided some evidence to confirm this: C9ORF72 was found to regulate endosomal trafficking and autophagy in neuronal cells and primary neurons.[27][30] 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.[31]

GTPase targets of a stable C9ORF72-SMCR8-WDR41 complex[32] include the Rag GTPases that simulate mTORC1 and so regulate macro-autophagy.[33][34] Also, C9ORF72 and SMCR8 regulate the function of lysosomes.[32] Although the GTPase involved on lysosomes is not yet identified, it might feasibly be Rab7A, which along with Rab5A and Rab11A, is activated by C9ORF72-SMCR8-WDR41 functioning as a GEF.[35]

As well as activating GTPases (GEF), the same C9ORF72-SMCR8-WDR41 complex is proposed to inactivate GTPases, i.e. as a GTPase activating protein (GAP). This activity is proposed for Rag GTPases, paralleling the Rag-GAP activity of the FLCN-FNIP complex,[32] which it resembles.[28] In addition, the complex is a GAP for Rab8a and Rab11a, with cryo-EM identifying an ariginine finger conserved between FLCN and SMCR8.[36]

Sequence analysis further suggests that the C9ORF72 protein emerged early in eukaryotic evolution, and whereas most eukaryotes usually possess a single copy of the gene encoding the C9ORF72 protein, the eukaryotes Entamoeba and Trichomonas vaginalis possess multiple copies, suggestive of independent lineage-specific expansions in these species. The family is lost in most fungi (except Rhizopus) and plants.[27][28]

Overall, the C9ORF72 mutation holds great promise for future therapies for familial FTD and/or ALS to be developed. Currently, there is focus on more research to be done on C9ORF72 to further understand the exact mechanisms involved in the cause of the diseases by this mutation. A clearer understanding of the exact pathogenic mechanism will aid in a more focused drug therapies. Possible drug targets currently include the repeat expansion itself as well as increasing levels of C9ORF72. Blocking the toxic gain of RNA foci to prevent RNA sequestration might be helpful as well as making up for the lack of C9ORF72. Either of these targets as well as a combination of them might be promising future targets in minimizing the effects of the C9ORF72 repeat expansion.[38]

C9ORF72 has been shown to interact with:

• ELAVL1,[39]
• UBC,[39] and
• ADARB2[40]

• Trinucleotide repeat disorder
• RAN translation

• Human C9orf72 genome location and C9orf72 gene details page in the UCSC Genome Browser.

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