User:Stheodoris

C9orf72 is a gene that produces the C9orf72 protein which is found in many regions of the brain. The purpose and structure of C9orf72 remain unclear, but it is found in the cytoplasm of neurons as well as in presynaptic terminals (nih.gov). The gene was first discovered by two independent research teams led by Bryan Traynor, M.D., Laboratory of Neurogenetics, National Institute on Aging, and Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, FL. The first research journals about the gene were published in 2011. The mutation on C9orf72 is significant because it is the first pathogenic mechanism identified to be a genetic link between familial frontotemporal dementia and amyotrophic lateral sclerosis. Thus far, it is the most common mutation identified that is associated with familial FTD and/or ALS.

Gene Location
The human C9ORF72 gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,542 to base pair 27,573,863. Its cytogenetic location is at 9p21.2.

Location of the C9orf72 gene on Chromosome 9.

Mutation
The mutation of C9orf72 is a hexanucleotide repeat expansion of the six letter string of nucleotides coded by GGGGCC. In a normal person, there are about 22 to 33 repeats of this hexanucleotide, but in people with the mutation, the repeat can occur in the order of hundreds. It is known that the mutation interferes with normal expression of the protein made by C9orf72, however the function of that protein is unknown. There are two possible major theories about the way that the C9orf72 mutation causes FTD and/or ALS. The first is that accumulation of RNA in the nucleus and cytoplasm becomes toxic and RNA sequestration occurs. The second theory is that the lack of the C9 protein itself causes the diseases. Of course, it is also considered that a combination of the two ways C9orf72 is interrupted might cause FTD and/or ALS.

Clinical Significance

 * first mutation found to present link between FTD and ALS
 * several studies showed commonality in both FTD and/or ALS
 * important for possible future therapy once the mechanism and function of the gene is better understood
 * current research being done on significant correlation to Motor Neuron Disease

FTD (Frontotemporal Dementia)

 * FTD is second most common form of early-onset demetia after Alzheimer’s disease
 * Different mutations of various genes have been linked to different phenotypes of FTD
 * C9 has been linked to semantic variant and nonfluent variant FTD
 * Also seen in BVFTD
 * Pathology in FTD seen to be caused with mutation include
 * TDP 43 in all C9 carriers
 * Type a,b,c,d amino reactivity
 * Type a-c seen in mutation
 * Type b is most common
 * Ubiquilin p62 protein degradation

ALS (Amyotrophic Lateral Sclerosis)

 * Amyotrophic Lateral Sclerosis is a neurodegenerative disorder that causes progressive muscle weakness, leading to difficulty walking, breathing, and speaking, and eventually is fatal
 * onset usually between 40-60 years old
 * Most common identifiable cause for ALS in patients with or without a family history of disease

ALS with FTD (ALS-FTD)

 * Important because currently the diagnosis of both FTD and ALS can take up to a year and many patients are misdiagnosed initially with another condition
 * A genetic link would help to diagnose the diseases faster

Gene Heritability

 * many studies have shown that it is most common in familial FTD and/or ALS
 * also found in sporadic ALS
 * include some statistics from references and different cohorts
 * paternal anticipation
 * thought to increase with each successive generation
 * disease might start up to a decade earlier with each successive generation
 * might be cause because expansion in DNA is unstable
 * several studies suggest that there is possibly one founder because of the high frequency of the mutation in cohorts in Northern Europe and Italy
 * at least a demographic factor that should be considered in genetic predisposition

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. There are also population and location risk factors in determining eligibility. Some studies have found that the mutation has a higher frequency in cohorts done in Italy and Northern Europe. Athena Diagnostics (Quest Diagnostics) announced in Spring 2012 the first clinically available testing service for detecting the hexanucleotide repeat expansion in the C9orf72 gene. Genetic counseling is recommended for the patients before a genetic test is ordered

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 sulcci 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.

Interactions
C9orf72 has been shown to interact with


 * ELAVL1
 * UBC