C9orf72

Last updated

C9orf72
Identifiers
Aliases C9orf72 , chromosome 9 open reading frame 72, ALSFTD, FTDALS, FTDALS1, DENNL72, C9orf72-SMCR8 complex subunit, DENND9
External IDs OMIM: 614260; MGI: 1920455; HomoloGene: 10137; GeneCards: C9orf72; OMA:C9orf72 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

203228

73205

Ensembl

ENSG00000147894

ENSMUSG00000028300

UniProt

Q96LT7

Q6DFW0

RefSeq (mRNA)

NM_145005
NM_001256054
NM_018325

NM_001081343
NM_028466

RefSeq (protein)

NP_001242983
NP_060795
NP_659442

NP_001074812
NP_082742

Location (UCSC) Chr 9: 27.54 – 27.57 Mb Chr 4: 35.19 – 35.23 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Contents

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 protein is found in many regions of the brain, in the cytoplasm of neurons as well as in presynaptic terminals. 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, and were first reported 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). It is the most common mutation identified that is associated with familial FTD and/or ALS in Caucasians. [8]

Evolutionary history

In humans the cytogenetic location was discovered in 2006 on 9p21.2. [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%). However, for the nematode Caenorhabditis elegans there is almost no correlation (14.71%) and there is none with Drosophila. [9]

Sequence analysis 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. [10] [11]

The molecular location on chromosome 9 is base pairs 27,546,546 to 27,573,866.

Mutations

The mutation of C9ORF72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC. [12] 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, [13] but in people with the mutation, the repeat number is between 30 and thousands. [14] 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. [15] [16] [17] The GGGGCC repeat expansion in C9orf72 is also believed to compromise nucleocytoplasmic transport through several possible mechanisms. [18]

Clinical significance

The C9ORF72 mutation is the first mutation found to be a link between familial FTD and ALS. [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. Frontotemporal dementia is the second most common form of early-onset dementia after Alzheimer's disease in people under the age of 65. [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. [21]

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 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. [22] Certain pathology in FTD caused by the C9orf72 mutation can also include:

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. [21] 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. [25] [26]

Gene heritability

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) [23] 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. [19] 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. [22] Haplotype is a specific combination of multiple polymorphic sites along a chromosomal region that is inherited together in a block. The correlation between C9orf72 haplotypes and GGGGCC repeat length was examined in Caucasians. The repeat length is largely constant in all haplotypes harboring up to 5 repeat units, but not in haplotype J, which typically harbors 6 repeats. The highest level of GGGGCC repeat length diversity is observed in haplotype R, which most frequently harbors 8 repeats. [27] The repeat length becomes more unstable with increasing length. The shortest documented GGGGCC repeat length change in subsequent generations was observed in a father and his daughter, who had 11 and 12 repeats, respectively. While all Caucasian C9orf72 patients are derived from a common founder that carried the R haplotype, it is unclear how many families in history experienced an expansion of repeat numbers from a normal length to a disease-associated length. In the Asian population, some C9orf72 ALS and FTD patients carry an alternative haplotype that is not related to the R haplotype.

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. [21] 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. [28] Athena Diagnostics (Quest Diagnostics) announced in Spring 2012 the first clinically available testing service for detecting the hexanucleotide repeat expansion in the C9orf72 gene. [29] 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"). [30] [10] [11] 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. [10] This led to DENNL72 being suggested as a new name for C9orf72. [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. Studies have provided some evidence to confirm this: C9ORF72 was found to regulate endosomal trafficking and autophagy in neuronal cells and primary neurons. [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. [33]

GTPase targets of a stable C9ORF72-SMCR8-WDR41 complex [34] include the Rag GTPases that simulate mTORC1 and so regulate macro-autophagy. [35] [36] Also, C9ORF72 and SMCR8 regulate the function of lysosomes. [34] 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. [37]

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, [34] which it resembles. [11] In addition, the complex is a GAP for Rab8a and Rab11a, with cryo-EM identifying an arginine finger conserved between FLCN and SMCR8. [38]

DNA damage response

Repeat sequence expansion mutations in C9orf72 that lead to neurodegeneration in ALS/FTD display dysfunction of the nucleolus and of R-loop formation. Such dysfunctions can lead to DNA damage. Motor neurons with C9orf72 mutations were found to activate the DNA damage response (DDR) as indicated by up-regulation of DDR markers. [39] If the DDR is insufficient to repair these DNA damages, apoptosis of the motor neurons is the likely result.

Primary cilium and hedgehog signaling

A 2023 PNAS paper showed that C9orf72–SMCR8 (Smith-Magenis syndrome 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 pathway. 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]

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. [41]

Interactions

C9ORF72 has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">Frontotemporal dementia</span> Types of dementia involving the frontal or temporal lobes

Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. FTD is the second most prevalent type of early onset dementia after Alzheimer's disease. Men and women appear to be equally affected. FTD generally presents as a behavioral or language disorder with gradual onset. Signs and symptoms tend to appear in late adulthood, typically between the ages of 45 and 65, although it can affect people younger or older than this. Currently, no cure or approved symptomatic treatment for FTD exists, although some off-label drugs and behavioral methods are prescribed.

<span class="mw-page-title-main">Frontotemporal lobar degeneration</span> Atrophy of the brains frontal and temporal lobes

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">Profilin 1</span> Protein-coding gene in the species Homo sapiens

Profilin-1 is a protein that in humans is encoded by the PFN1 gene.

<span class="mw-page-title-main">PURA</span> Protein-coding gene in the species Homo sapiens

Pur-alpha is a protein that in humans is encoded by the PURA gene located at chromosome 5, band q31.

<span class="mw-page-title-main">ALS2</span> Protein-coding gene in the species Homo sapiens

Alsin is a protein that in humans is encoded by the ALS2 gene. ALS2 orthologs have been identified in all mammals for which complete genome data are available.

<span class="mw-page-title-main">TAR DNA-binding protein 43</span> Protein found in humans

TAR DNA-binding protein 43 is a protein that in humans is encoded by the TARDBP gene.

<span class="mw-page-title-main">TMEM106B</span> Protein-coding gene in humans

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.

<span class="mw-page-title-main">CCNF</span> Protein-coding gene in humans

G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.

<span class="mw-page-title-main">ALS</span> Rare neurodegenerative disease

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease in the United States, is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and lower motor neurons that normally control voluntary muscle contraction. ALS is the most common form of the motor neuron diseases. ALS often presents in its early stages with gradual muscle stiffness, twitches, weakness, and wasting. Motor neuron loss typically continues until the abilities to eat, speak, move, and, lastly, breathe are all lost. While only 15% of people with ALS also fully develop frontotemporal dementia, an estimated 50% face at least some minor difficulties with thinking and behavior. Depending on which of the aforementioned symptoms develops first, ALS is classified as limb-onset or bulbar-onset.

Project MinE is an independent large scale whole genome research project that was initiated by 2 patients with amyotrophic lateral sclerosis and started on World ALS Day, June 21, 2013.

Multisystem proteinopathy (MSP) is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and/or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders. Historically, several different names have been used to describe MSP, most commonly "inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD)" or "inclusion body myopathy with frontotemporal dementia, Paget's disease of bone, and amyotrophic lateral sclerosis (IBMPFD/ALS)." However, IBMPFD and IBMPFD/ALS are now considered outdated classifications and are more properly referred to as MSP, as the disease is clinically heterogeneous and its phenotypic spectrum extends beyond IBM, PDB, FTD, and ALS to include motor neuron disease, Parkinson's disease features, and ataxia features. Although MSP is rare, growing interest in this syndrome derives from the molecular insights the condition provides into the etiological relationship between common age-related degenerative diseases of muscle, bone, and brain.

Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial, also known as Protein N27C7-4 is a protein that in humans is encoded by the CHCHD10 gene.

RNA-dominant diseases are characterized by deleterious mutations that typically result in degenerative disorders affecting various neurological, cardiovascular, and muscular functions. Studies have found that they arise from repetitive non-coding RNA sequences, also known as toxic RNA, which inhibit RNA-binding proteins leading to pathogenic effects. The most studied RNA-dominant diseases include, but are not limited to, myotonic dystrophy and fragile X-associated tremor/ataxia syndrome (FXTAS).

<span class="mw-page-title-main">UNC13A</span> Protein-coding gene in the species Homo sapiens

Unc-13 homolog A is a protein that in humans is encoded by the UNC13A gene.

There are more than 25 genes known to be associated with amyotrophic lateral sclerosis (ALS) as of June 2018, which collectively account for about 70% of cases of familial ALS (fALS) and 10% of cases of sporadic ALS (sALS). About 5–10% of cases of ALS are directly inherited. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.

Research on amyotrophic lateral sclerosis (ALS) has focused on animal models of the disease, its mechanisms, ways to diagnose and track it, and treatments.

Bryan J. Traynor is a neurologist and a senior investigator at the National Institute on Aging, and an adjunct professor at Johns Hopkins University. Dr. Traynor studies the genetics of human neurological conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). He led the international consortium that identified pathogenic repeat expansions in the C9orf72 gene as a common cause of ALS and FTD. Dr. Traynor also led efforts that identified other Mendelian genes responsible for familial ALS and dementia, including VCP, MATR3, KIF5A, HTT, and SPTLC1.

Rosa Rademakers is a Dutch neurogeneticist and professor within the Department of Neuroscience at the Mayo Clinic. Her research centers on the genetic basis of neurodegenerative diseases, such as identifying causal genes and their function, exploring familial risk factors, and the mechanism of the degeneration. Her neurodegenerative diseases of focus include "Alzheimer's disease (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)." She received a Bachelor of Arts in Biology, a Master of Arts in Biochemistry, and a Ph.D. in Science, all from the University of Antwerp. Originally from the Netherlands, she came to the Mayo Clinic in 2005 for a post-doctoral fellowship, and in 2007 she was given a lab director position.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000147894 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028300 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ C9orf72 chromosome 9 open reading frame 72 [Homo sapiens] - Gene - NCBI
  6. ↑ DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (October 2011). "Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS". Neuron. 72 (2): 245–56. doi:10.1016/j.neuron.2011.09.011. PMC   3202986 . PMID   21944778.
  7. ↑ Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. (October 2011). "A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD". Neuron. 72 (2): 257–68. doi:10.1016/j.neuron.2011.09.010. PMC   3200438 . PMID   21944779.
  8. ↑ Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G (2019). "C9orf72 Hexanucleotide Repeat Expansion". Behavioural Neurology. 2019: 2909168. doi: 10.1155/2019/2909168 . PMC   6350563 . PMID   30774737.
  9. 1 2 Smeyers J, Banchi EG, Latouche M (5 May 2021). "C9ORF72: What It Is, What It Does, and Why It Matters". Frontiers in Cellular Neuroscience. 15: 661447. doi: 10.3389/fncel.2021.661447 . ISSN   1662-5102. PMC   8131521 . PMID   34025358.
  10. 1 2 3 4 Zhang D, Iyer LM, He F, Aravind L (2012). "Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease". Frontiers in Genetics. 3: 283. doi: 10.3389/fgene.2012.00283 . PMC   3521125 . PMID   23248642.
  11. 1 2 3 4 Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (February 2013). "The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs". Bioinformatics. 29 (4): 499–503. doi:10.1093/bioinformatics/bts725. PMC   3570213 . PMID   23329412.
  12. ↑ Bigio EH (December 2011). "C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology". Acta Neuropathologica. 122 (6): 653–5. doi:10.1007/s00401-011-0919-7. PMC   3262229 . PMID   22101324.
  13. ↑ Fong JC, Karydas AM, Goldman JS (2012). "Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion". Alzheimer's Research & Therapy. 4 (4): 27. doi: 10.1186/alzrt130 . PMC   3506941 . PMID   22808918.
  14. ↑ Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. (April 2012). "Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (4): 358–64. doi:10.1136/jnnp-2011-301883. PMC   3388906 . PMID   22399793.
  15. ↑ Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. (March 2013). "The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS". Science. 339 (6125): 1335–8. Bibcode:2013Sci...339.1335M. doi: 10.1126/science.1232927 . PMID   23393093. S2CID   32244381.
  16. ↑ Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. (February 2013). "Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS". Neuron. 77 (4): 639–46. doi:10.1016/j.neuron.2013.02.004. PMC   3593233 . PMID   23415312.
  17. ↑ Balendra R, Isaacs AM (September 2018). "C9orf72-mediated ALS and FTD: multiple pathways to disease". Nature Reviews. Neurology. 14 (9): 544–558. doi:10.1038/s41582-018-0047-2. PMC   6417666 . PMID   30120348.
  18. ↑ Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, et al. (September 2015). "GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport". Nature. 525 (7567): 129–33. Bibcode:2015Natur.525..129F. doi:10.1038/nature14974. PMC   4631399 . PMID   26308899.
  19. 1 2 Cruts M, Engelborghs S, van der Zee J, Van Broeckhoven C (1993). "C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   25577942.
  20. ↑ Ratnavalli E, Brayne C, Dawson K, Hodges JR (June 2002). "The prevalence of frontotemporal dementia". Neurology. 58 (11): 1615–21. doi:10.1212/WNL.58.11.1615. PMID   12058088. S2CID   45904851.
  21. 1 2 3 Herdewyn S, Zhao H, Moisse M, Race V, Matthijs G, Reumers J, et al. (June 2012). "Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis". Human Molecular Genetics. 21 (11): 2412–9. doi:10.1093/hmg/dds055. PMC   3349421 . PMID   22343411.
  22. 1 2 Friedland RP, Shah JJ, Farrer LA, Vardarajan B, Rebolledo-Mendez JD, Mok K, Hardy J (2012). "Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat". Frontiers in Neurology. 3: 136. doi: 10.3389/fneur.2012.00136 . PMC   3463813 . PMID   23060854.
  23. 1 2 Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, et al. (March 2012). "Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72". Brain. 135 (Pt 3): 765–83. doi:10.1093/brain/aws004. PMC   3286335 . PMID   22366793.
  24. ↑ Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, et al. (March 2012). "Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features". Brain. 135 (Pt 3): 736–50. doi:10.1093/brain/awr361. PMC   3286330 . PMID   22366791.
  25. ↑ Otomo A, Pan L, Hadano S (2012). "Dysregulation of the autophagy-endolysosomal system in amyotrophic lateral sclerosis and related motor neuron diseases". Neurology Research International. 2012: 498428. doi: 10.1155/2012/498428 . PMC   3407648 . PMID   22852081.
  26. ↑ Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. (January 2014). "C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies". Neurology. 82 (4): 292–9. doi:10.1212/WNL.0000000000000061. PMC   3929197 . PMID   24363131.
  27. ↑ Ben-Dor I, Pacut C, Nevo Y, Feldman EL, et al. (March 2021). "Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing". PLOS Genet. 17 (3): e1009445. doi: 10.1371/journal.pgen.1009445 . PMC   8031855 . PMID   33780440.
  28. ↑ Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, et al. (September 2012). "The genetics and neuropathology of frontotemporal lobar degeneration". Acta Neuropathologica. 124 (3): 353–72. doi:10.1007/s00401-012-1029-x. PMC   3422616 . PMID   22890575.
  29. ↑ New Testing for ALS Archived 26 June 2012 at the Wayback Machine (2012)
  30. ↑ Söding J, Biegert A, Lupas AN (July 2005). "The HHpred interactive server for protein homology detection and structure prediction". Nucleic Acids Research. 33 (Web Server issue): W244-8. doi:10.1093/nar/gki408. PMC   1160169 . PMID   15980461.
  31. ↑ Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA (October 2010). "Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors". The Journal of Cell Biology. 191 (2): 367–81. doi:10.1083/jcb.201008051. PMC   2958468 . PMID   20937701.
  32. ↑ Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, et al. (July 2014). "C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking". Human Molecular Genetics. 23 (13): 3579–95. doi:10.1093/hmg/ddu068. PMC   4049310 . PMID   24549040.
  33. ↑ O'Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AK, et al. (March 2016). "C9orf72 is required for proper macrophage and microglial function in mice". Science. 351 (6279): 1324–9. Bibcode:2016Sci...351.1324O. doi:10.1126/science.aaf1064. PMC   5120541 . PMID   26989253.
  34. 1 2 3 Amick J, Tharkeshwar AK, Amaya C, Ferguson SM (September 2018). Barr FA (ed.). "WDR41 supports lysosomal response to changes in amino acid availability". Molecular Biology of the Cell. 29 (18): 2213–2227. doi:10.1091/mbc.E17-12-0703. PMC   6249801 . PMID   29995611.
  35. ↑ Wang M, Wang H, Tao Z, Xia Q, Hao Z, Prehn JH, et al. (April 2020). "C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis". Aging Cell. 19 (4): e13126. doi:10.1111/acel.13126. PMC   7189992 . PMID   32100453.
  36. ↑ Ji YJ, Ugolino J, Zhang T, Lu J, Kim D, Wang J (April 2020). Kao A (ed.). "C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases". PLOS Genetics. 16 (4): e1008738. doi: 10.1371/journal.pgen.1008738 . PMC   7188304 . PMID   32282804.
  37. ↑ Iyer S, Subramanian V, Acharya KR (17 October 2018). "C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor". PeerJ. 6: e5815. doi: 10.7717/peerj.5815 . PMC   6195791 . PMID   30356970.
  38. ↑ Tang D, Sheng J, Xu L, Zhan X, Liu J, Jiang H, et al. (May 2020). "Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a". Proceedings of the National Academy of Sciences of the United States of America. 117 (18): 9876–9883. Bibcode:2020PNAS..117.9876T. doi: 10.1073/pnas.2002110117 . PMC   7211967 . PMID   32303654.
  39. ↑ Farg MA, Konopka A, Soo KY, Ito D, Atkin JD (August 2017). "The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis". Human Molecular Genetics. 26 (15): 2882–2896. doi: 10.1093/hmg/ddx170 . PMID   28481984.
  40. ↑ Tang D, Zheng K, Zhu J, Jin X, Bao H, Jiang L, et al. (December 2023). "ALS-linked C9orf72–SMCR8 complex is a negative regulator of primary ciliogenesis". Proceedings of the National Academy of Sciences of the United States of America. 120 (50): e2220496120. Bibcode:2023PNAS..12020496T. doi: 10.1073/pnas.2220496120 . PMC   10723147 . PMID   38064514.
  41. ↑ Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, et al. (March 2012). "Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics". Brain. 135 (Pt 3): 794–806. doi:10.1093/brain/aws001. PMC   3286334 . PMID   22366795.
  42. 1 2 "C9orf72 Interaction Summary". BioGRID.
  43. ↑ Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Heusler AR, Mistry NA, et al. (October 2013). "RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention". Neuron. 80 (2): 415–28. doi:10.1016/j.neuron.2013.10.015. PMC   4098943 . PMID   24139042.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.