C9orf72

C9orf72 (chromosome 9 open reading frame 72) is a protein which in humans is encoded by the gene C9orf72.

The human C9orf72 gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,546 to base pair 27,573,866 (GRCh38). Its cytogenetic location is at 9p21.2.^[5]

The

The mutation of C9ORF72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC.[9] In approximately half of all alleles, the hexanucleotide repeat is repeated twice, and in over 98% of the alleles its length is less than 17 repeats,^[10] but in people with the mutation, the repeat number is between 30 and thousands.^[11] There are three major theories about the way that the C9ORF72 mutation causes FTD and/or ALS. One theory is that accumulation of RNA that carry the expanded repeat in the nucleus and cytoplasm becomes toxic due to sequestration of RNA binding proteins. 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. 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 variant 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]

Clinical significance

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 mutation 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

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, including Huntington's disease.^[22][23]

Gene heritability

It is possible that

Gene testing

Since this mutation has been found to be the most common mutation identified in familial FTD and/or ALS, it is considered one of if not the most dependable candidates for genetic testing. Patients are considered eligible if the mother or father has had FTD and/or another family member has had ALS.^[18] There are also population and location risk factors in determining eligibility. Some studies have found that the mutation has a higher frequency in certain cohorts.^[25] Athena Diagnostics (Quest Diagnostics) announced in Spring 2012 the first clinically available testing service for detecting the hexanucleotide repeat expansion in the C9orf72 gene.^[26] Genetic counseling is recommended for the patients before a genetic test is ordered.

Likely function of C9ORF72 protein

C9ORF72 is predicted to be a full-length homologue of DENN proteins (where DENN stands for "differentially expressed in normal and neoplastic cells").^[27][28][29] 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.^[28] This led to DENNL72 being suggested as a new name for C9orf72.^[29]

Given the molecular role of known DENN modules,

The recent 2023 published PNAS paper shows that C9orf72–SMCR8 (Smith-Magenis chromosome region 8) complex suppresses primary cilium growth as a RAB8A GAP (GTPase activating protein), establishing a link between C9orf72 function and the primary cilium and hedgehog signaling. 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. This discovery sheds light on a potential pathogenic mechanism related to the loss of C9orf72 function.[39]

Evolutionary history

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.^[28][29]

Implications for future therapies

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.^[40]

Interactions

C9ORF72 has been shown to interact with:

• ELAVL1,^[41]
• UBC,^[41]
  and
• ADARB2^[42]

See also

• Trinucleotide repeat disorder
• RAN translation

References

External links

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

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