Alternative titles; symbols
SNOMEDCT: 1259124000; ORPHA: 275872; DO: 0060213;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p21.2 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 | 105550 | Autosomal dominant | 3 | C9orf72 | 614260 |
A number sign (#) is used with this entry because of evidence that this form of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS1) is caused by a heterozygous hexanucleotide repeat expansion (GGGGCC) in a noncoding region of the C9ORF72 gene (614260) on chromosome 9p21. Unaffected individuals have 2 to 19 repeats, whereas affected individuals have 250 to over 2,000 repeats. However, some individuals can show symptoms with as few as 20 to 22 repeats (summary by Reddy et al., 2013; Gomez-Tortosa et al., 2013).
Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by Vance et al., 2006). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by Harms et al., 2013). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013; Gomez-Tortosa et al., 2013).
Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of FTDALS, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration.
For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see 600274. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1 (ALS1; 105400).
Genetic Heterogeneity of Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis
See also FTDALS2 (615911), caused by mutation in the CHCHD10 gene (615903) on chromosome 22q11; FTDALS3 (616437), caused by mutation in the SQSTM1 gene (601530) on chromosome 5q35; FTDALS4 (616439), caused by mutation in the TBK1 gene (604834) on chromosome 12q14; FTDALS5 (619141), caused by mutation in the CCNF gene (600227) on chromosome 16p13; FTDALS6 (613954), caused by mutation in the VCP gene (601023) on chromosome 9p13; FTDALS7 (600795), caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; and FTDALS8 (619132), caused by mutation in the CYLD gene (605018) on chromosome 16q12.
Pinsky et al. (1975) described amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) as an entity distinct from pure ALS because dementia is absent in the latter condition. They found considerable intrafamilial variability. Lesions in the cerebral cortex had a distinctive frontotemporal distribution. Another family was reported by Finlayson et al. (1973), and the families reported by Dazzi and Finizio (1969) and Robertson (1953) may have had the same condition.
Hosler et al. (2000) described several families with ALS and FTD. In family F222, 1 patient was diagnosed with ALS and FTD, while 2 showed only motor neuron symptoms. For 3 other persons, the clinical records and other available information confirmed the diagnosis of ALS accompanied by dementia symptoms but were inconclusive as to the type of dementia. In family F17, 2 patients were diagnosed with ALS and FTD, while 2 had ALS alone. One patient had ALS accompanied by dementia symptoms. The mean age of onset for affected individuals in these 2 families was 53.8 +/- 8.2 years, with a range of 40 to 62 years, and an average duration of 3.8 +/- 4.0 years, with a range of 1.3 to 15 years. Most persons survived 4 years or less, and 1 patient survived 15 years. The dementia specified as FTD in these families was characterized by socially inappropriate, impulsive behavior and general deterioration in ability to perform routine daily tasks. These behavioral changes occurred months before any significant changes in memory. Examination of these patients documented a combination of corticospinal and lower motor neuron features in conjunction with signs of frontal release. Imaging studies were consistent with frontotemporal atrophy. Pathologic studies confirmed the presence of frontotemporal atrophy and also revealed frontotemporal gliosis, vacuolar changes in the corresponding cortex, rare Pick bodies, and a relative paucity of amyloid plaques and neurofibrillary tangles. Hosler et al. (2000) concluded that these combined findings fulfill the Lund-Manchester criteria for a diagnosis of FTD arising concurrently with motor neuron disease.
Morita et al. (2006) reported a 4-generation Scandinavian kindred in which 5 individuals were diagnosed with amyotrophic lateral sclerosis and 9 with frontotemporal dementia. No individual had both diagnoses. Those with ALS presented with motor neuron symptoms, but 3 later developed subtle cognitive dysfunction. Those with dementia showed progressive cognitive deficits without significant memory loss and had no signs of motor impairment. Two individuals with FTD showed loss of spinal cord neurons at autopsy. Given the clinical and pathologic overlap of ALS and FTD and the observation that both disorders reflect neurodegenerative processes, Morita et al. (2006) concluded that the disorders in this family represent pleiotropic manifestations of a single gene defect.
Vance et al. (2006) reported a large Dutch family in which 10 individuals had ALS. The family had originally been reported by Ruddy et al. (2003) as family F2. Five patients had bulbar onset, and 5 had limb onset. Age of onset ranged from 40 to 72 years with a mean survival of 3 years. Inheritance was autosomal dominant with reduced penetrance. Three patients who presented with motor symptoms of ALS subsequently developed personality and behavioral changes, including apathy, social isolation, emotional lability, and hallucinations. Postmortem examination of 4 patients showed significant upper and lower motor neuron degeneration. One female patient presented at age 39 with progressive personality changes and dementia and subsequently developed muscle wasting and fasciculations consistent with ALS. She died of respiratory failure after 31 months, and postmortem examination showed frontal lobe atrophy and shrunken motor neurons.
Valdmanis et al. (2007) reported 3 unrelated families with ALS and/or FTD. In a Canadian family, 5 individuals had ALS only, and 3 had FTD only. Five individuals from a family of Spanish origin had ALS; 1 of these patients had also shown early signs of FTD. A third family of French Canadian origin included 5 individuals with ALS only and 3 with ALS and FTD.
Luty et al. (2008) reported a 3-generation Australian family of Anglo-Celtic origin in which 11 individuals had FTD and/or MND. Five presented with the behavioral variant of FTD, 2 presented with progressive bulbar and limb weakness consistent with MND, 2 presented with a combination of FTD and MND, and 2 had nonspecific dementia, diagnosed as Alzheimer disease (AD; 104300) in 1. The average age at onset was 53 years. Neuropathologic examination of 1 patient with FTD and the patient with a clinical diagnosis of AD showed abnormal TDP43 (TARDBP; 605078)-positive inclusions in neurons of the frontal cortex and hippocampus; examination of a patient with MND showed degeneration of the corticospinal tracts and TDP43-positive inclusions in anterior horn cells.
Le Ber et al. (2009) identified 6 new families with FTD and/or motor neuron disease showing linkage to chromosome 9p. The mean age at onset was 57.9 years, and the mean disease duration was 3.6 years. The phenotype was heterogeneous both among and within families: 32% of patients presented with isolated FTD, 29% with isolated MND, and 39% with both disorders. Motor neuron disease presented as upper limb motor deficit and amyotrophy in most patients (68%), and bulbar symptoms were present in 32% of patients. FTD was consistent with a behavioral variant. Brain MRI showed bilateral predominantly frontotemporal atrophy, and neuropathologic examination of 3 patients showed neuronal loss in various brain regions and spinal cord. All patients had cytoplasmic neuronal ubiquitin (UBB; 191339)-positive, tau (MAPT; 157140)-negative cytoplasmic inclusions in the cortex and spinal cord. TDP43-positive neuronal inclusions were also found.
Boxer et al. (2011) reported a large 4-generation family of Irish ancestry with FTD and/or ALS. Five individuals had the behavioral variant of FTD, 2 with mild parkinsonism, 2 had limb-onset ALS, and 3 had both disorders. One patient had apraxia and parkinsonism, consistent with a corticobasal syndrome. Age at onset ranged from 35 to 57 years, with a mean of 45.7, and the mean disease duration was 5.4 years. Brain imaging showed reduced cortical volume, particularly affecting the frontal lobes. Neuropathologic study of 3 patients showed chronic degenerative changes with neuronal loss, reactive gliosis, and superficial laminar spongiosis. The corticospinal tracts showed decreased myelin staining. Immunohistochemical studies showed TDP43-immunoreactive cytoplasmic inclusions in neurons, and to a lesser extent, in glial cells. Some neuronal inclusions and neurites stained for p62 (SQSTM1; 601530) and ubiquitin, but not TDP43.
Pearson et al. (2011) reported a family originating from South Wales with this disorder. There were 9 affected individuals showing variable phenotypes. The average age at onset was 42.2 years, with a duration of 3.6 years. Five (62.5%) presented with ALS, with bulbar and/or limb onset; 1 also had FTD and 3 later developed FTD. Three (37.5%) patients presented with behavioral variant FTD and later developed ALS. Other variable features included psychosis, hallucinations, delusions, visuospatial dysfunction, extrapyramidal signs, and parkinsonism. One patient had cerebellar ataxia. Neuropathology showed many TDP43-positive neuronal cytoplasmic inclusions.
FTDALS, confirmed by the identification of a hexanucleotide repeat expansion in the C9ORF72 gene, was reported in a Brazilian kindred of Italian and Portuguese origin (Takada et al., 2012); in 4 families from Canada and France (Daoud et al., 2012); and in 3 members of a family from the United States (Savica et al., 2012). Three of the families reported by Daoud et al. (2012) had previously been reported by Valdmanis et al. (2007). Intrafamilial phenotypic variation was apparent in all reports. Features included the behavioral variant of FTD, ALS, and parkinsonism: 1 or all 3 of these disorders could be found in an affected individual. Some more variable features included visual hallucinations, focal dystonia, and posterior brain atrophy (Takada et al., 2012); levodopa-unresponsive parkinsonism (Savica et al., 2012); and isolated ALS without dementia (Daoud et al., 2012). Of the 36 affected individuals in the families reported by Daoud et al. (2012), 18 (50%) had ALS, 5 (13.8%) had FTD, 7 (19.4%) had ALS/FTD, and 6 (16.6%) had preliminary signs of dementia. The average age at onset was 60 years. The patients reported by Takada et al. (2012) had expanded alleles of 5 to 23 kb. The exact sizes of the expanded alleles could not be determined by the methods used in the reports of Daoud et al. (2012) and Savica et al. (2012).
Lindquist et al. (2013) identified a pathogenic C9ORF72 expansion in 14 (5%) of 280 unrelated hospitalized Danish patients referred for genetic testing for inherited dementia disorders. Ten patients had a diagnosis of FTD or FTD-ALS, 1 had ALS, and 3 had atypical diagnoses, including olivopontocerebellar degeneration, corticobasal syndrome, and atypical Parkinson syndrome with FTD-ALS. All except 1 patient had a family history of a similar disorder. The findings expanded the clinical spectrum associated with C9ORF72 mutations.
Gomez-Tortosa et al. (2013) reported 9 Spanish FTD probands with expanded C9ORF72 repeats. Six of the patients had significant psychiatric symptoms, most commonly depression, as long as several decades before the onset of dementia. Brain MRI showed frontotemporal atrophy in 7 of 9 patients.
Meisler et al. (2013) reported a parent and child of Northern European ancestry with bipolar disorder associated with a C9ORF72 repeat expansion. The proband was identified from a cohort of 89 patients with bipolar disorder who underwent screening for the C9ORF72 repeat expansion. The 35-year-old proband developed typical bipolar disorder at age 25 years and showed normal executive function and memory ability at age 35. The affected parent developed bipolar disorder and mood irregularities at age 62, and was subsequently diagnosed with FTD. The parent also developed a gait disorder and had parkinsonian features at age 66; the parent died at age 69. Postmortem examination showed frontotemporal atrophy and some neuropathologic changes consistent with Alzheimer disease, including tau pathology and ubiquitinated cytoplasmic inclusions. Southern blot analysis of peripheral blood from the proband identified a 2,600 repeat expansion (between 14 and 20 kb), whereas the parent carried shorter expansions (8.5 to 20 kb). Cultured lymphoblast cell lines from the parent were enriched for the shorter 8.5-kb expansion length, suggesting that there may be selection for the shorter repeat in cultured cells. The genetic and clinical findings were suggestive of genetic anticipation, as well as etiologic relationship between the C9ORF72 expansion and disease progression from bipolar disorder to FTD.
Hensman Moss et al. (2014) identified a pathologic C9ORF72 repeat expansion in 10 (1.95%) of 514 patients from the United Kingdom who initially presented with clinical features suggestive of Huntington disease (HD; 143100), but who were negative for a pathologic repeat expansion in the HTT gene (613004). These patients were classified as having an 'HD phenocopy' syndrome. Of these 10 patients, 70% had a positive family history for a neurodegenerative disease. The mean age at onset in these patients was 42.7 years, and 6 presented with psychiatric and/or behavioral problems. Movement disorders, including chorea, dystonia, myoclonus, tremor, rigidity, and bradykinesia, were prominent features. Cognitive impairment, executive dysfunction, and/or memory problems were present in all patients. The expansion size of the repeat could be determined in 8 patients, and ranged from 2,939 to 4,010 repeats. Hensman Moss et al. (2014) concluded that a C9ORF72 repeat expansion is the most common genetic cause of HD phenocopy syndrome in European populations, and that screening for this expansion should be included in an algorithm for the workup of HD.
By genomewide linkage analysis of a large Scandinavian family considering ALS or FTD as different phenotypic manifestations of a single genetic defect, Morita et al. (2006) identified a candidate locus on chromosome 9p21.3-p13.3 (maximum multipoint lod score of 3.00 between D9S1121 and D9S2154). Haplotype analysis delineated a 21.8-cM region between D9S1870 and D9S1791. Sequencing analysis of the VCP (601023) and UBQLN1 (605046) genes showed no abnormalities.
In a large Dutch family with ALS and/or FTD, Vance et al. (2006) found linkage to chromosome 9p; fine mapping yielded a maximum multipoint lod score of 3.02 at D9S1874. Haplotype analysis identified a 12-cM region between markers D9S2154 and D9S1874 on chromosome 9p21.3-p13.2. The family had originally been reported by Ruddy et al. (2003) as family F2 with apparent linkage to chromosome 16q. Vance et al. (2006) noted that the report of Morita et al. (2006) overlapped precisely with their locus and reduced the shared region to 9.8 Mb.
Valdmanis et al. (2007) found evidence suggesting linkage to chromosome 9p in 3 unrelated families with ALS and/or FTD who were analyzed separately. Combining the results of all 3 families yielded a maximum multipoint lod score of 7.22 for a 15.1-cM interval between D9S1121 and D9S1791. No mutations were identified in the TEK gene (600221).
By genomewide linkage analysis of an Australian family with FTD and/or MND, Luty et al. (2008) found significant linkage to a 9.6-cM region on chromosome 9p (2-point lod score of 3.24 and multipoint lod score of 3.41 at D9S1817). The disease haplotype spanned 57 Mb between chromosome 9p21-9q12, and partially overlapped previously reported loci.
By linkage analysis of 6 families with FTD and/or MND, Le Ber et al. (2009) found a cumulative multipoint lod score of 8.0 at marker D9S248 between markers D9S1121 and D9S301 on chromosome 9p. Haplotype reconstruction defined a 7.7-Mb region between D9S1817 and AFM218xg11. There were no disease-causing mutations in 29 candidate genes, including IFT74, and no copy number variations in the 9p region. There was no evidence for a founder effect among these families.
Van Es et al. (2009) conducted a genomewide association study among 2,323 individuals with sporadic ALS and 9,013 control subjects and evaluated all SNPs with P less than 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Two SNPs at chromosome 9p21.2 showed significant association in the replication phase and genomewide significance in the combined analysis: rs2814707, p = 7.45 x 10(-9) and rs3849942, p = 1.01 x 10(-8). These SNPs are located in a linkage region for familial ALS with frontotemporal dementia found by Valdmanis et al. (2007), Morita et al. (2006), and Vance et al. (2006) in several large pedigrees.
By genomewide linkage analysis of a large family with FTD/ALS, Boxer et al. (2011) found linkage to a 28.3-cM region between D9S1808 and D9S251 on chromosome 9p (2-point lod score of 3.01 at D9S1870). Comparison with previous reports allowed refinement of the region to a 3.7-Mb interval. Pearson et al. (2011) identified a 4.8-Mb haplotype on 9p21.2-9p21.1 that was shared by all affected members of a family from Wales with FTD/ALS.
The transmission pattern of FTDALS1 in the families reported by DeJesus-Hernandez et al. (2011) and Renton et al. (2011) was consistent with autosomal dominant inheritance.
Hosler et al. (2000) conducted a genomewide linkage analysis involving 16 informative pedigrees. In the course of this screening, they identified a locus at chromosome 9q21-q22 in 2 families with FTD and/or ALS. One family, F222, had a lod score of 1.10 at theta of 0.0 for marker D9S922 and a score of 0.48 at theta of 0.0 for marker D9S1122. A second family, F17, had lod scores of 2.08, 0.07, and 3.15 with markers D9S301, D9S1122, and D9S922, respectively, at theta of 0.0. In the other 14 families in this linkage analysis subset, which showed no linkage to these markers on chromosome 9q21-q22, there were no individuals with both ALS and FTD. The locus on 9q identified by Hosler et al. (2000) has not been replicated (Mackenzie and Rademakers, 2007).
Molecular Diagnosis
Akimoto et al. (2014) found significant differences in the accuracy of genetic testing for the pathologic C9ORF72 repeat expansion in a blinded international study of 14 laboratories that tested 78 samples. Using PCR-based techniques, only 5 of the 14 laboratories obtained results in full accordance with Southern blotting results (gold standard). Only 50 of the 78 DNA samples obtained the same genotype result in all 14 laboratories. Sensitivity and specificity greater than 95% was reached in only 7 (50%) of the laboratories. Akimoto et al. (2014) recommended using a combination of amplicon-length analysis and repeat-primed PCR (RP-PCR) as a minimum standard in a research setting. However, Southern blotting techniques should be made obligatory in a clinical diagnostic setting.
Using a nonradioactive Southern blot protocol, Dols-Icardo et al. (2014) characterized the C9ORF72 hexanucleotide repeat expansion in 38 ALS and 22 FTD patients who were found by PCR to have over 30 copies of the repeat. Overall, patients with ALS had a significantly higher number of repeats compared to those with FTD, although there was a substantial amount of overlap. There was no correlation between number of repeats and age at onset or disease duration. For ALS and FTD, the median size of the minimum repeat was 1,082 and 916, respectively, and the median size of the maximum repeat was 2,245 and 1,666, respectively. Repeat number in 1 patient with FTD was moderately higher in cerebellar tissue compared to peripheral blood, and repeat number was higher in a monozygotic twin with ALS compared to his twin without ALS.
In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTD/ALS) mapping to chromosome 9p21, DeJesus-Hernandez et al. (2011) and Renton et al. (2011) simultaneously and independently identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene (614260.0001). The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded to 700 to 1,600 (DeJesus-Hernandez et al., 2011) or 250 repeats (Renton et al., 2011) in patients. DeJesus-Hernandez et al. (2011) identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat. Renton et al. (2011) found the expanded repeat in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases from Finland, as well as in 38.1% of 268 familial ALS probands of European origin. Both DeJesus-Hernandez et al. (2011) and Renton et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of DeJesus-Hernandez et al. (2011), transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism.
Millecamps et al. (2012) identified expanded repeats in intron 1 of the C9ORF72 gene in 46% of 225 French patients with familial ALS, 7% of 725 French patients with sporadic ALS, and in none of 580 controls. The expanded repeat was shown to segregate with the disorder in 16 families, although there were some unaffected obligate carriers, suggesting incomplete penetrance. An expanded C9ORF72 repeat was defined as greater than 50 repeats. Compared to ALS patients with mutations in other genes, those with the C9ORF72 repeat had later age at onset, showed more frequent bulbar involvement, more often had FTD, and showed shorter disease duration. The findings confirmed that the C9ORF72 repeat expansion plays a major role in ALS.
Belzil et al. (2013) identified a hexanucleotide repeat expansion in the C9ORF72 gene in 13 (52%) of 25 patients of Caucasian origin with ALS who had a family history of cognitive impairment.
Gomez-Tortosa et al. (2013) identified expanded C9ORF72 repeats in 9 (8.2%) of 109 Spanish probands with FTD. Four patients had more than 30 repeats, whereas 4 had 20 repeats and 1 had 22 repeats. None of the other 100 cases had greater than 13 repeats, and none of 216 controls had more than 14 repeats. In 4 families, the expanded 20- or 22-repeat alleles segregated consistently in all affected sibs, with the unaffected sibs having wildtype alleles (2-9 repeats). The 20- or 22-repeat allele was associated with the surrogate marker of the founder haplotype in all cases. Most of the 9 expansion carriers had extended periods with psychiatric symptoms and subjective cognitive complaints before clear neurologic deterioration, and there was no phenotypic difference between those with longer or shorter expansions. These findings suggested that short C9ORF72 hexanucleotide expansions in the 20- to 22-repeat range are also related to FTD.
Harms et al. (2013) found C9ORF72 hexanucleotide expansions in 55 (6.9%) of 797 patients with sporadic ALS from the United States. The frequency of expansions was significantly higher in the Midwest (9.2%) compared to the Pacific Northwest (3.0%). Mutation carriers had an earlier age at onset compared to nonmutation carriers (55.9 versus 59.2 years), and were more likely than noncarriers to have a family history of dementia. Two (0.4%) of 526 neurologically normal Caucasian controls also carried an expansion. Repeat expansions were also found in 22 (43%) of 51 patients with familial ALS. Fibroblast cell lines available from 9 patients showed expanded repeats between 600 and 800 units. Two individuals had additional smaller expanded alleles, suggesting somatic instability. DNA derived from occipital cortex was available for 2 additional patients and showed much larger expansions (1,600 repeat units), suggesting that expansions are larger within neuronal tissues. Sequencing of the coding exons of the C9ORF72 gene in 389 ALS patients yielded no pathogenic mutations, suggesting a gain-of-function mechanism rather than a loss-of-function mechanism.
Van Blitterswijk et al. (2013) detected C9ORF72 repeat expansions in 4 (1.2%) of 334 individuals who carried pathogenic mutations in genes associated with a neurodegenerative disease. Three of the patients carried mutations in the GRN gene (138945) and 1 had a mutation in the MAPT gene (157140). All 4 patients had the behavioral variant of FTD. Postmortem examination of 1 of the patients who carried both a GRN mutation and a C9ORF72 expansion showed mixed neuropathology with characteristics of both genetic defects. The findings indicated that some cases of FTD may be due to an oligogenic effect, and suggested that the cooccurrence of 2 pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. Van Blitterswijk et al. (2013) concluded that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
Using Southern blot analysis, Nordin et al. (2015) investigated the size of the C9ORF72 repeat expansion in different tissues from 18 autopsied patients with ALS and/or FTD who had repeat expansions in peripheral blood. There was tissue-specific variability in all patients, suggesting that certain properties of each tissue could influence the size of the expansion. In 2 patients, the size variation was extreme: repeats in all nonneural tissues examined were below 100, whereas expansions in neural tissues were 20 to 40 times greater. There was no correlation between expansion size in the frontal lobe and occurrence of cognitive impairment.
Associations Pending Confirmation
In affected members of the family with FTD and/or MND reported by Luty et al. (2008), Luty et al. (2010) identified a putative pathogenic heterozygous G-to-T transversion (672*51G-T) in the 3-prime untranslated region (UTR) of the SIGMAR1 gene (601978) on chromosome 9p13. In vitro functional expression studies in human neuroblastoma, HEK293 cells, and patient lymphocytes showed that the substitution resulted in about 2-fold increased expression of SIGMAR1 compared to wildtype, and neuropathologic study of affected individuals showed increased SIGMAR1 protein in frontal cortex tissue. Studies of brain tissue from controls and from individuals with unrelated form of FTLD showed that sigma-1 was localized on membranes within the cytoplasm of most neurons, astrocytes, and oligodendroglia, whereas in 2 patients with the 672*51G-T mutation, it was concentrated within the nucleus of degenerating neurons. Patients with the SIGMAR1 mutation also had TDP43- and FUS-positive inclusions in affected brain regions, although in different neuronal populations. Overexpression of SIGMAR1 in cell lines resulted in increased levels of TDP43 protein, but not TDP43 transcripts, and caused a change in localization of TDP43 from the nucleus to the cytoplasm. Luty et al. (2010) postulated that the 672*51G-T transversion, which occurs in the 3-prime UTR of the SIGMAR1 gene, alters transcript stability and increases gene expression, resulting in increased pathogenic alterations of TDP43 and FUS. However, the authors noted that the SIGMAR1 gene may not represent the major locus for FTLD/MND that maps to chromosome 9p. Luty et al. (2010) also reported an unrelated patient from another Australian family (AUS-47) with frontotemporal dementia without motor neuron disease who carried a heterozygous c.672*26C-T transition in the SIGMAR1 gene, and an unrelated patient from a Polish family (POL-1) with a diagnosis of Alzheimer disease and aphasia who carried a heterozygous c.672*47G-A transition. Both variants occurred in the 3-prime UTR of the SIGMAR1 gene and were absent from 169 elderly controls and 1,110 normal controls, but segregation analysis in these 2 families was not possible. Neither patient had motor neuron disease. Dobson-Stone et al. (2013) noted that the AUS-14 family reported by Luty et al. (2010) also carried a pathogenic expansion in the C9ORF72 gene (614260.0001) that segregated with the disorder and was thus likely responsible for the phenotype. However, Dobson-Stone et al. (2013) excluded a pathogenic expansion of the C9ORF72 gene in the proband of the AUS-47 family. Pickering-Brown and Hardy (2015) commented that the disease in the AUS-14 family reported by Luty et al. (2010) was likely caused by the C9ORF72 expansion rather than the SIGMAR1 variant, and questioned the role of SIGMA1 variants in FTD/MND.
Belzil et al. (2013) did not identify any coding or noncoding variants in the SIGMAR1 gene among 25 patients with ALS and a family history of dementia. A G-to-T transversion (672*43G-T) in the 3-prime untranslated region was found in 1 patient, but this was also found in 1 of 190 controls. Moreover, the C9ORF72 repeat expansion was subsequently identified in this patient and in 52% of the entire cohort. Belzil et al. (2013) suggested that the SIGMAR1 variants identified by Luty et al. (2010) actually segregated with C9ORF72 expansions, and that SIGMAR1 variants are not a cause of ALS with dementia.
Xi et al. (2014) reported a pair of Caucasian Semitic monozygotic twin sisters with an expanded C9ORF72 repeat who were discordant for ALS. One twin developed bulbar-onset ALS at age 57 years and had no cognitive impairment. At age 62, the other twin had no symptoms of ALS but did have mild cognitive deficits on testing, particularly in verbal fluency, abstraction, and executive function, which could represent early signs of dementia. Southern blot analysis of blood samples showed expanded C9ORF72 repeats of 800 and 1,350, with the difference likely due to somatic instability. Neither twin had increased methylation at the 5-prime CpG island.
Xi et al. (2015) reported a British Canadian family in which a clinically unaffected 89-year-old man had a 70-repeat mildly expanded C9ORF72 allele that expanded significantly to about 1,750 repeats during transmission to 4 of his offspring, who ranged in age from 51 to 65 years of age. However, only 2 of the 4 sibs with the expanded allele were affected with FTDALS, which Xi et al. (2015) attributed to clinical variability and variable age at onset. Epigenetic and RNA-expression analyses showed that the large expansions in the offspring were methylated and associated with decreased C9ORF72 expression, whereas the 70-repeat allele in the father was unmethylated and associated with upregulation of C9ORF72. Fibroblasts from the offspring with large expansions showed RNA foci, which were not found in the father. Postmortem tissue from 1 of the affected offspring showed variation in the expansion among tissues studied, suggesting somatic instability. Xi et al. (2015) concluded that the 70-repeat expansion allele is not pathogenic and suggested that there should be a better low cut-off for a pathogenic repeat number. However, small expansions could be considered premutations because of the potential instability during transmission. In addition, the findings supported a hypothesis of multiple origins for the expansion rather than a single founder effect.
Using 2 methods, Xi et al. (2013) investigated the CpG methylation profile of genomic DNA from the blood of individuals with ALS, including 37 G4C2 expansion carriers and 64 noncarriers, 76 normal controls, and family members of 7 ALS patients with the expansion. Hypermethylation of the CpG island 5-prime of the G4C2 repeat was associated with the presence of the expansion (p less than 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p less than 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Methylation changes were not detected in either normal or intermediate alleles (up to 43 repeats), raising the question of whether the cutoff of 30 repeats for pathologic alleles was adequate. The findings suggested that pathogenic repeat expansion of the G4C2 allele in C9ORF72 may lead to epigenetic changes, such as gene expression silencing, that may be associated with disease.
Using electrophoresis, Reddy et al. (2013) found that nonpathogenic lengths of the C9ORF72 repeat RNA r(GGGGCC) (2 to 19 units) form extremely stable uni- and multimolecular structures called G-quadruplexes. Increasing concentration of RNA or number of repeats increased the formation of the G-quadruplexes. The r(GGGGCC)4 repeat bound the splicing factor SRSF1 (600812) in vivo. The complementary C-rich r(CCCCGG) did not form such complexes. G-quadruplex structures are associated with several biologic processes, including gene regulation, splicing, and RNA translation regulation. The location of the r(GGGGCC) repeat within a noncoding region of the C9ORF72 gene suggests that it may play a role in the normal function of the transcript. Pathogenic expansion of the repeat may contribute to the formation of toxic ribonuclear foci via the formation of hairpin structures or abnormal binding of additional proteins.
Donnelly et al. (2013) generated induced pluripotent stem cells (iPSCs) from fibroblasts derived from ALS patients with a pathogenic expanded C9ORF72 repeat and reprogrammed them to differentiate into neuronal cells. These neuronal cells, which retained the expanded repeat, showed decreased levels of C9ORF72 RNA compared to controls, as well as toxic intranuclear expanded GGGGCC RNA foci. Decreased C9ORF72 RNA and toxic RNA foci were also found in brain tissue derived from patients with the mutation. Toxic cytoplasmic protein foci were also observed in cells and tissue, indicating that the expanded repeat RNA undergoes non-ATG-initiated translation. A proteome array and immunofluorescence analysis showed that the RNA-binding protein ADARB2 (602065) interacts with the C9ORF72 GGGGCC repeat; toxic foci in patient cells comprised the expanded pathogenic repeat and sequestered ADARB2. Patient iPSCs showed enhanced glutamate sensitivity, which may have been related to ADARB2 sequestration. Transcriptome analysis of patient cells and tissue showed dysregulation of several genes compared to controls. Treatment of the cells with antisense oligonucleotides to C9ORF72 reduced the number of toxic RNA foci, attenuated nuclear accumulation of ADARB2, normalized the dysregulated gene expression of some targeted candidate biomarker genes, and partially rescued the glutamate toxicity of these cells. These findings indicated that RNA toxicity plays a key role in C9ORF72 ALS.
Ciura et al. (2013) found decreased C9ORF72 gene expression in cells and tissue derived from ALS/FTD patients carrying the pathogenic expanded repeat. Decreased C9ORF72 expression was also found in brain samples of 8 patients with ALS/FTD who did not carry the C9ORF72 expansion, suggesting that this gene may play a wider role in the etiology of this neurodegenerative disorder.
Haeusler et al. (2014) identified a molecular mechanism by which structural polymorphism of the C9ORF72 hexanucleotide repeat expansion (HRE) leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA/DNA hybrids (R-loops). The structural polymorphism causes a repeat length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin (164035) preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Haeusler et al. (2014) concluded that distinct C9ORF72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Both the sense and antisense transcripts of the GGGGCC repeats associated with C9ORF72 can be translated in an ATG-independent manner (without an ATG start codon) known as repeat-associated non-ATG (RAN) translation (Mori et al., 2013). The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9ORF72 gene altered in neurodegenerative disease encode glycine:arginine (GR(n)) and proline:arginine (PR(n)) repeat polypeptides, respectively. Kwon et al. (2014) found that both peptides bound to hnRNPA2 (see 600124) hydrogels. When applied to cultured cells, both GR(20) and PR(20) peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.
Mizielinska et al. (2014) developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted 'RNA-only' repeats, in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine; GR) and poly-(proline-arginine; PR) proteins caused neurodegeneration. Mizielinska et al. (2014) concluded that their findings were consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9ORF72-mediated neurodegeneration.
To discover RNA-binding proteins that genetically modify GGGGCC (G4C2)-mediated neurogenesis, Zhang et al. (2015) performed a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats. They identified RanGAP (the Drosophila ortholog of human RanGAP1, 602362), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppressed neurodegeneration. RanGAP physically interacted with HRE RNA and was mislocalized in HRE-expressing flies, neurons from C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9ORF72 ALS patient brain tissue. Nuclear import was impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Zhang et al. (2015) suggested that nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Freibaum et al. (2015) generated transgenic flies expressing 8, 28, or 58 G4C2 repeat-containing transcripts that did not have a translation start site but contained an open reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. Freibaum et al. (2015) showed that these transgenic animals display dosage-dependent, repeat length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat proteins, as observed in patients with C9ORF72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, Freibaum et al. (2015) found morphologic abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, the authors identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged iPSC-derived neurons from patients with C9ORF72-related disease. Freibaum et al. (2015) concluded that their studies showed that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.
Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease (143100), spinocerebellar ataxia (e.g., 164400), myotonic dystrophy (e.g., 160900), and FTDALS1. In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease.
McCauley et al. (2020) found that blood-derived macrophages, whole blood, and brain tissue from patients with FTDALS1 exhibited an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD. Moreover, this increased interferon response could be suppressed with an inhibitor of STING (612374), a key regulator of the innate immune response to cytosolic DNA. McCauley et al. (2020) concluded that these findings, as well as their findings in C9orf72 mutant mice, suggested that patients with FTDALS1 have an altered immunophenotype because reduced levels of C9ORF72 cannot suppress inflammation mediated by induction of type I interferons by STING.
Kramer et al. (2016) found that targeting Spt4 (orthologous to SUPT4H1; 603555) selectively decreased production of both sense and antisense expanded transcripts of C9orf72, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1 similarly decreased production of sense and antisense RNA foci and DPR proteins in patient cells. The authors argued that single-factor targeting has advantages over targeting sense and antisense repeats separately.
In a genomewide association analysis of 442 Finnish ALS patients and 521 controls, Laaksovirta et al. (2010) identified a disease association with SNP rs3849942 on chromosome 9p21 (p = 9.11 x 10(-11)). A 42-SNP haplotype was associated with a significantly increased risk of ALS (odds ratio of 21.0, p = 7.47 x 10(-33)) when those with familial ALS were compared to controls. For familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9%. About 3% of the patients with this risk haplotype developed FTD. The findings were consistent with a founder effect in this homogeneous population.
Mok et al. (2012) found that a smaller founder disease haplotype, located within that identified in the Finnish population by Laaksovirta et al. (2010), was present in ALS families from other populations of northern European descent, including Irish, UK, and US, but not in Italians. The findings suggested that most individuals with the disease carry the same pathogenic variant.
Ishiura et al. (2012) identified a pathogenic repeat expansion in the C9ORF72 gene in 3 (20%) of 15 patients with ALS from the southernmost Kii peninsula of Japan in the Wakayama prefecture neighboring the Koza River. The patients did not have parkinsonism, and only 1 had moderate cognitive decline. Haplotype analysis indicated a founder effect, with a shared haplotype spanning 3.3-63 Mb; this haplotype overlapped the Finnish founder haplotype by 130 kb and was shared by another Japanese patient with ALS from another area of Japan. C9ORF72 expansions were not found in 6 ALS patients from a more northern Wakayama region or in 16 patients with ALS and 16 patients with parkinsonism-dementia complex (PDC) in the more northern Mie prefecture/Hohara district of the Kii peninsula. The findings suggested that part of the known ALS-PDC phenotype prevalent among Japanese from the Kii peninsula (105500) is caused by an expanded C9ORF72 repeat.
In a large population-based study of Caucasian individuals from the Netherlands, van Rheenen et al. (2012) identified an expanded C9ORF72 hexanucleotide repeat (over 30 repeats) in 33 (37%) of 78 probands with familial ALS, 87 (6.1%) of 1,422 patients with sporadic ALS, 4 (1.6%) of 246 patients with a diagnosis of progressive muscular atrophy, and 1 (0.9%) of 110 patients with a diagnosis of primary lateral sclerosis. None of 768 control individuals carried a repeat expansion. Patients with ALS due to the expansion had a higher incidence of family members with dementia compared to all patients with ALS or to controls. All patients had tested negative for mutations in the SOD1 (147450), TARDBP (605078), and FUS (137070) genes, and the C9ORF72 repeat expansions were determined by a repeat primed PCR method.
Garcia-Redondo et al. (2013) identified a pathogenic intron 1 C9ORF72 hexanucleotide repeat expansion (defined as more than 30 repeats) (614260.0001) in 42 (27.1%) of 155 Spanish patients with familial ALS and in 25 (3.2%) of 781 Spanish patients with sporadic ALS. Thus, this mutation was the most common genetic cause of ALS in the Spanish population, followed by SOD1 (147450) mutations, which account for 18% of familial ALS and 1% of sporadic ALS. Haplotype analysis indicated a founder effect for the pathogenic expansion allele. One ALS patient with 28 repeats was identified, and his allele was on the founder disease haplotype. The most common nonpathogenic allele in both patients and controls was 2 repeats; none of 248 controls carried the expansion mutation. C9ORF72 mutation carriers had a lower age at onset, frequent concurrence with FTD, and shorter survival when compared to ALS patients without the expansion. Analysis of other ethnic populations showed that this haplotype was present in 5.6% Yoruba African, 8.9% European CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
Van der Zee et al. (2013) assessed the distribution of C9ORF72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort of 1,205 individuals ascertained by the European Early-Onset Dementia (EOD) consortium. A metaanalysis of the data and that of other European studies, including a total of 2,668 patients from 15 countries, showed that the frequency of C9ORF72 expansions in western Europe was 9.98% in FTLD, with 18.52% in familial and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of 29.33% and 20.73%, respectively, consistent with the hypothesis of a Scandinavian founder effect. However, Spain also showed a high frequency of the expansion, at 25.49%. In contrast, the prevalence in Germany was low, at 4.82%. The phenotype was most often characterized by behavioral disturbances (95.7%). Postmortem examination of a small number of cases showed TDP43 (605078) and p62 (601530) deposits in the brain. Intermediate repeats (7 to 24 repeat units) were found to be strongly correlated with the risk haplotype tagged by a T allele of SNP rs2814707. In vitro reporter gene expression studies showed significantly decreased transcriptional activity of C9ORF72 with increasing number of normal repeat units, consistent with a loss of function. This was also observed with intermediate repeats, suggesting that they might act as predisposing alleles. There was also a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the expanded repeat in expansion carriers, suggesting that pathologic expansion may be due to replication slippage.
Smith et al. (2013) identified the expanded hexanucleotide repeat in C9ORF72 in 226 (17%) of 1,347 patients with ALS with or without FTD collected from 5 European populations in whom known ALS genes had been excluded. The expansion was also observed in 3 (0.3%) of 856 controls, yielding an odds ratio (OR) of 57 (p = 4.12 x 10(-47)), but also indicating incomplete penetrance. The highest frequency of the mutation was in familial cases of ALS+FTD (48/67, 72%), but it was also prevalent in pure ALS families (89/228, 39%), with the total familial frequency being 46% (OR of 244, p = 6.13 x 10(-89)). Frequencies of the expansion in familial ALS+FTD showed variation by country: 19/22 (86%) in Belgium, 30/41 (73%) in Sweden, 10/27 (37%) in the Netherlands, 73/185 (39%) in England, and 4/20 (20%) in Italy. Haplotype analysis identified a common 82-SNP disease haplotype in the majority of 137 cases studied, indicating a single common founder in these European populations. The mutation was estimated to have arisen 6,300 years ago. The disease haplotype was found in almost 15% of European controls. The average number of pathogenic repeats on the disease haplotype was 8, with a spread of expanded alleles up to 26. The most prevalent number of repeats on other haplotypes was 2. The findings suggested that the background disease haplotype is intrinsically unstable, tending to generate longer repeats. In a subset of 296 ALS patients with or without FTD from London, the C9ORF72 expanded repeat was found in 26%, followed by mutations in SOD1 (147450) (24%), FUS (137070) (4%), and TARDPB (605078) (1%). Overall, the findings showed that the C9ORF72 expanded repeat is the most common genetic cause of ALS with or without FTD across Europe.
Using repeat-primed PCR, Beck et al. (2013) identified 96 repeat-primed PCR expansions in a large population- and patient-based cohort: there were 85 (2.9%) expansions among 2,974 patients with various neurodegenerative diseases and 11 (0.15%) expansions among 7,579 controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in patients was 800 to 4,400. Large expansions were also detected in the population controls. There were some differences in expansion size and morphology between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. The findings suggested that there may be a higher prevalence of expanded C9ORF72 repeat carriers than previously thought.
Ciura et al. (2013) found expression of the C9orf72 gene in the brain and spinal cord of zebrafish embryos. Morpholino knockdown of C9orf72 in zebrafish resulted in disrupted neuronal arborization and shortening of the motor neuron axons compared to controls, as well as motor deficits. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts. These results revealed a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease.
Akimoto, C., Volk, A. E., van Blitterswijk, M., Van den Broeck, M., Leblond, C. S., Lumbroso, S., Camu, W., Neitzel, B., Onodera, O., van Rheenen, W., Pinto, S., Weber, M., and 31 others. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories. J. Med. Genet. 51: 419-424, 2014. [PubMed: 24706941] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102360]
Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R. W., Malaspina, A., and 15 others. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am. J. Hum. Genet. 92: 345-353, 2013. [PubMed: 23434116] [Full Text: https://doi.org/10.1016/j.ajhg.2013.01.011]
Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A. Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia. Europ. J. Hum. Genet. 21: 237-239, 2013. [PubMed: 22739338] [Full Text: https://doi.org/10.1038/ejhg.2012.135]
Boxer, A. L., Mackenzie, I. R., Boeve, B. F., Baker, M., Seeley, W. W., Crook, R., Feldman, H., Hsiung, G.-Y. R., Rutherford, N., Laluz, V., Whitwell, J., Foti, D., McDade, E., Molano, J., Karydas, A., Wojtas, A., Goldman, J., Mirsky, J., Sengdy, P., DeArmond, S., Miller, B. L., Rademakers, R. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J. Neurol. Neurosurg. Psychiat. 82: 196-203, 2011. [PubMed: 20562461] [Full Text: https://doi.org/10.1136/jnnp.2009.204081]
Ciura, S., Lattante, S., Le Ber, I., Latouche, M., Tostivint, H., Brice, A., Kabashi, E. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann. Neurol. 74: 180-187, 2013. [PubMed: 23720273] [Full Text: https://doi.org/10.1002/ana.23946]
Daoud, H., Suhail, H., Sabbagh, M., Belzil, V., Szuto, A., Dionne-Laporte, A., Khoris, J., Camu, W., Salachas, F., Meininger, V., Mathieu, J., Strong, M., Dion, P. A., Rouleau, G. A. C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia. Arch. Neurol. 69: 1159-1163, 2012. [PubMed: 22964911] [Full Text: https://doi.org/10.1001/archneurol.2012.377]
Dazzi, P., Finizio, F. S. Sulla sclerosa laterale amiotrofica familiare. Contributo clinico. G. Psychiat. Neuropath. 97: 299-337, 1969.
DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., and 16 others. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: 245-256, 2011. [PubMed: 21944778] [Full Text: https://doi.org/10.1016/j.neuron.2011.09.011]
Dobson-Stone, C., Hallupp, M., Loy, C. T., Thompson, E. M., Haan, E., Sue, C. M., Panegyres, P. K., Razquin, C., Seijo-Martinez, M., Rene, R., Gascon, J., Campdelacreu, J., Schmoll, B., Volk, A. E., Brooks, W. S., Schofield, P. R., Pastor, P., Kwok, J. B. J. C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients. PLoS One 8: e56899, 2013. Note: Electronic Article. [PubMed: 23437264] [Full Text: https://doi.org/10.1371/journal.pone.0056899]
Dols-Icardo, O., Garcia-Redondo, A., Rojas-Garcia, R., Sanchez-Valle, R., Noguera, A., Gomez-Tortosa, E., Pastor, P., Hernandez, I., Esteban-Perez, J., Suarez-Calvet, M., Anton-Aguirre, S., Amer, G., and 13 others. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Molec. Genet. 23: 749-754, 2014. [PubMed: 24057670] [Full Text: https://doi.org/10.1093/hmg/ddt460]
Donnelly, C. J., Zhang, P.-W., Pham, J. T., Haeusler, A. R., Mistry, N. A., Vidensky, S., Daley, E. L., Poth, E. M., Hoover, B., Fines, D. M., Maragakis, N., Tienari, P. J., Petrucelli, L., Traynor, B. J., Wang, J., Rigo, F., Bennett, C. F., Blackshaw, S., Sattler, R., Rothstein, J. D. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80: 415-428, 2013. Note: Erratum: Neuron 80: 1102 only, 2013. [PubMed: 24139042] [Full Text: https://doi.org/10.1016/j.neuron.2013.10.015]
Finlayson, M. H., Guberman, A., Martin, J. B. Cerebral lesions in familial amyotrophic lateral sclerosis and dementia. Acta Neuropath. 26: 237-246, 1973. [PubMed: 4769153] [Full Text: https://doi.org/10.1007/BF00684433]
Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., Taylor, J. P. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525: 129-133, 2015. [PubMed: 26308899] [Full Text: https://doi.org/10.1038/nature14974]
Garcia-Redondo, A., Dols-Icardo, O., Rojas-Garcia, R., Esteban-Perez, J., Cordero-Vazquez, P., Munoz-Blanco, J. L., Catalina, I., Gonzalez-Munoz, M., Varona, L., Sarasola, E., Povedano, M., Sevilla, T., and 11 others. Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide. Hum. Mutat. 34: 79-82, 2013. [PubMed: 22936364] [Full Text: https://doi.org/10.1002/humu.22211]
Gomez-Tortosa, E., Gallego, J., Guerrero-Lopez, R., Marcos, A., Gil-Neciga, E., Sainz, M. J., Diaz, A., Franco-Macias, E., Trujillo-Tiebas, M. J., Ayuso, C., Perez-Perez, J. C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology 80: 366-370, 2013. [PubMed: 23284068] [Full Text: https://doi.org/10.1212/WNL.0b013e31827f08ea]
Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., Rothstein, J. D., Wang, J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195-200, 2014. [PubMed: 24598541] [Full Text: https://doi.org/10.1038/nature13124]
Harms, M. B., Cady, J., Zaidman, C., Cooper, P., Bali, T., Allred, P., Cruchaga, C., Baughn, M., Libby, R. T., Pestronk, A., Goate, A., Ravits, J., Baloh, R. H. Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis. Neurobiol. Aging 34: e13-e19, 2013. Note: Electronic Article. [PubMed: 23597494] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2013.03.006]
Hensman Moss, D. J., Poulter, M., Beck, J., Hehir, J., Polke, J. M., Campbell, T., Adamson, G., Mudanohwo, E., McColgan, P., Haworth, A., Wild, E. J., Sweeney, M. G., Houlden, H., Mead, S., Tabrizi, S. J. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 82: 292-299, 2014. Note: Erratum: Neurology 82: 1753 only, 2014. [PubMed: 24363131] [Full Text: https://doi.org/10.1212/WNL.0000000000000061]
Hosler, B. A., Siddique, T., Sapp, P. C., Sailor, W., Huang, M. C., Hossain, A., Daube, J. R., Nance, M., Fan, C., Kaplan, J., Hung, W.-Y., McKenna-Yasek, D., Haines, J. L., Pericak-Vance, M. A., Horvitz, H. R., Brown, R. H., Jr. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284: 1664-1669, 2000. [PubMed: 11015796] [Full Text: https://doi.org/10.1001/jama.284.13.1664]
Ishiura, H., Takahashi, Y., Mitsui, J., Yoshida, S., Kihira, T., Kokubo, Y., Kuzuhara, S., Ranum, L. P. W., Tamaoki, T., Ichikawa, Y., Date, H., Goto, J., Tsuji, S. C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan. Arch. Neurol. 69: 1154-1158, 2012. [PubMed: 22637429] [Full Text: https://doi.org/10.1001/archneurol.2012.1219]
Jain, A., Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546: 243-247, 2017. [PubMed: 28562589] [Full Text: https://doi.org/10.1038/nature22386]
Kramer, N. J., Carlomagno, Y., Zhang, Y.-J., Almeida, S., Cook, C. N., Gendron, T. F., Prudencio, M., Van Blitterswijk, M., Belzil, V., Couthouis, J., Paul, J. W., III, Goodman, L. D., and 24 others. Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353: 708-712, 2016. [PubMed: 27516603] [Full Text: https://doi.org/10.1126/science.aaf7791]
Kwon, I., Xiang, S., Kato, M., Wu, L., Theodoropoulos, P., Wang, T., Kim, J., Yun, J., Xie, Y., McKnight, S. L. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345: 1139-1145, 2014. [PubMed: 25081482] [Full Text: https://doi.org/10.1126/science.1254917]
Laaksovirta, H., Peuralinna, T., Schymick, J. C., Scholz, S. W., Lai, S.-L., Myllykangas, L., Sulkava, R., Jansson, L., Hernandez, D. G., Gibbs, J. R., Nalls, M. A., Heckerman, D., Tienari, P. J., Traynor, B. J. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9: 978-985, 2010. [PubMed: 20801718] [Full Text: https://doi.org/10.1016/S1474-4422(10)70184-8]
Le Ber, I., Camuzat, A., Berger, E., Hannequin, D., Laquerriere, A., Golfier, V., Seilhean, D., Viennet, G., Couratier, P., Verpillat, P., Heath, S., Camu, W., and 15 others. Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 72: 1669-1676, 2009. [PubMed: 19433740] [Full Text: https://doi.org/10.1212/WNL.0b013e3181a55f1c]
Lindquist, S. G., Duno, M., Batbayli, M., Puschmann, A., Braendgaard, H., Mardosiene, S., Svenstrup, K., Pinborg, L. H., Vestergaard, K., Hjermind, L. E., Stokholm, J., Andersen, B. B., Johannsen, P., Nielsen, J. E. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin. Genet. 83: 279-283, 2013. [PubMed: 22650353] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01903.x]
Luty, A. A., Kwok, J. B. J., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann. Neurol. 68: 639-649, 2010. [PubMed: 21031579] [Full Text: https://doi.org/10.1002/ana.22274]
Luty, A. A., Kwok, J. B. J., Thompson, E. M., Blumbergs, P., Brooks, W. S., Loy, C. T., Dobson-Stone, C., Panegyres, P. K., Hecker, J., Nicholson, G. A., Halliday, G. M., Schofield, P. R. Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 8: 32, 2008. Note: Electronic Article. [PubMed: 18755042] [Full Text: https://doi.org/10.1186/1471-2377-8-32]
Mackenzie, I. R. A., Rademakers, R. The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments. Neurogenetics 8: 237-248, 2007. [PubMed: 17805587] [Full Text: https://doi.org/10.1007/s10048-007-0102-4]
McCauley, M. E., O'Rourke, J. G., Yanez, A., Markman, J. L., Ho, R., Wang, X., Chen, S., Lall, D., Jin, M., Muhammad, A. K. M. G., Bell, S., Laderos, J., Valencia, V., Harms, M., Arditi, M., Jefferies, C., Baloh, R. H. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature 585: 96-101, 2020. [PubMed: 32814898] [Full Text: https://doi.org/10.1038/s41586-020-2625-x]
Meisler, M. H., Grant, A. E., Jones, J. M., Lenk, G. M., He, F., Todd, P. K., Kamali, M., Albin, R. L., Lieberman, A. P., Langenecker, S. A., McInnis, M. G. C9ORF72 expansion in a family with bipolar disorder. Bipolar Disorders 15: 326-332, 2013. [PubMed: 23551834] [Full Text: https://doi.org/10.1111/bdi.12063]
Millecamps, S., Boillee, S., Le Ber, I., Seilhean, D., Teyssou, E., Giraudeau, M., Moigneu, C., Vandenberghe, N., Danel-Brunaud, V., Corcia, P., Pradat, P.-F., Le Forestier, N., Lacomblez, L., Bruneteau, G., Camu, W., Brice, A., Cazeneuve, C., LeGuern, E., Meininger, V., Salachas, F. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. J. Med. Genet. 49: 258-263, 2012. [PubMed: 22499346] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100699]
Mizielinska, S., Gronke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., Cleverley, K., Nicoll, A. J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E. M. C., Partridge, L., Isaacs, A. M. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345: 1192-1194, 2014. [PubMed: 25103406] [Full Text: https://doi.org/10.1126/science.1256800]
Mok, K., Traynor, B. J, Schymick, J., Tienari, P. J., Laaksovirta, H., Peuralinna, T., Myllykangas, L., Chio, A., Shatunov, A., Boeve, B. F., Boxer, A. L., DeJesus-Hernandez, M., and 18 others. The chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol. Aging 33: 209e3-209e8, 2012. Note: Electronic Article. [PubMed: 21925771] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2011.08.005]
Mori, K., Weng, S.-M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Van Broeckhoven, C., Haass, C., Edbauer, D. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339: 1335-1338, 2013. [PubMed: 23393093] [Full Text: https://doi.org/10.1126/science.1232927]
Morita, M., Al-Chalabi, A., Andersen, P. M., Hosler, B., Sapp, P., Englund, E., Mitchell, J. E., Habgood, J. J., de Belleroche, J., Xi, J., Jongjaroenprasert, W., Horvitz, H. R., Gunnarsson, L.-G., Brown, R. H., Jr. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66: 839-844, 2006. [PubMed: 16421333] [Full Text: https://doi.org/10.1212/01.wnl.0000200048.53766.b4]
Nordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Jonsson, P., Birve, A., Marklund, S. L., Graffmo, K. S., Forsberg, K., Brannstrom, T., Andersen, P. M. Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum. Molec. Genet. 24: 3133-3142, 2015. [PubMed: 25712133] [Full Text: https://doi.org/10.1093/hmg/ddv064]
Pearson, J. P., Williams, N. M., Majounie, E., Waite, A., Stott, J., Newsway, V., Murray, A., Hernandez, D., Guerreiro, R., Singleton, A. B., Neal, J., Morris, H. R. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J. Neurol. 258: 647-655, 2011. [PubMed: 21072532] [Full Text: https://doi.org/10.1007/s00415-010-5815-x]
Pickering-Brown, S., Hardy, J. Is SIGMAR1 a confirmed FTD/MND gene? (Letter) Brain 138: e393, 2015. Note: Electronic Article. [PubMed: 26088964] [Full Text: https://doi.org/10.1093/brain/awv173]
Pinsky, L., Finlayson, M. H., Libman, I., Scott, B. H. Familial amyotrophic lateral sclerosis with dementia: a second Canadian family. Clin. Genet. 7: 186-191, 1975. [PubMed: 1139787] [Full Text: https://doi.org/10.1111/j.1399-0004.1975.tb00317.x]
Ranganathan, R., Haque, S., Coley, K., Shepheard, S., Cooper=Knock, J., Kirby, J. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front. Neurosci. 14: 684, 2020. Note: Electronic Article. [PubMed: 32733193] [Full Text: https://doi.org/10.3389/fnins.2020.00684]
Reddy, K., Zamiri, B., Stanley, S. Y. R., Macgregor, R. B, Jr., Pearson, C. E. The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J. Biol. Chem. 288: 9860-9866, 2013. [PubMed: 23423380] [Full Text: https://doi.org/10.1074/jbc.C113.452532]
Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., and 65 others. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72: 257-268, 2011. [PubMed: 21944779] [Full Text: https://doi.org/10.1016/j.neuron.2011.09.010]
Robertson, E. E. Progressive bulbar paralysis showing heredofamilial incidence and intellectual impairment. Arch. Neurol. Psychiat. 69: 197-207, 1953.
Ruddy, D. M., Parton, M. J., Al-Chalabi, A., Lewis, C. M., Vance, C., Smith, B. N., Leigh, P. N., Powell, J. F., Siddique, T., Meyjes, E. P., Baas, F., De Jong, V., Shaw, C. E. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am. J. Hum. Genet. 73: 390-396, 2003. [PubMed: 12840784] [Full Text: https://doi.org/10.1086/377157]
Savica, R., Adeli, A., Vemuri, P., Knopman, D. S., DeJesus-Hernandez, M., Rademakers, R., Fields, J. A., Whitwell, J., Jack, C. R., Jr., Lowe, V., Petersen, R. C., Boeve, B. F. Characterization of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. Arch. Neurol. 69: 1164-1169, 2012. [PubMed: 22637471] [Full Text: https://doi.org/10.1001/archneurol.2012.772]
Smith, B. N., Newhouse, S., Shatunov, A., Vance, C., Topp, S., Johnson, L., Miller, J., Lee, Y., Troakes, C., Scott, K. M., Jones, A., Gray, I., and 34 others. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Europ. J. Hum. Genet. 21: 102-108, 2013. [PubMed: 22692064] [Full Text: https://doi.org/10.1038/ejhg.2012.98]
Takada, L. T., Pimentel, M. L. V., DeJesus-Hernandez, M., Fong, J. C., Yokoyama, J. S., Karydas, A., Thibodeau, M.-P., Rutherford, N. J., Baker, M. C., Lomen-Hoerth, C., Rademakers, R., Miller, B. L. Frontotemporal dementia in a Brazilian kindred with the C9orf72 mutation. Arch. Neurol. 69: 1149-1153, 2012. [PubMed: 22964910] [Full Text: https://doi.org/10.1001/archneurol.2012.650]
Valdmanis, P. N., Dupre, N., Bouchard, J.-P., Camu, W., Salachas, F., Meininger, V., Strong, M., Rouleau, G. A. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch. Neurol. 64: 240-245, 2007. Note: Erratum: Arch. Neurol. 64: 909 only, 2007. [PubMed: 17296840] [Full Text: https://doi.org/10.1001/archneur.64.2.240]
van Blitterswijk, M., Baker, M. C., DeJesus-Hernandez, M., Ghidoni, R., Benussi, L., Finger, E., Hsiung, G.-Y. R., Kelley, B. J., Murray, M. E., Rutherford, N. J., Brown, P. E., Ravenscroft, T., and 21 others. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 81: 1332-1341, 2013. [PubMed: 24027057] [Full Text: https://doi.org/10.1212/WNL.0b013e3182a8250c]
van der Zee, J., Gijselinck, I., Dillen, L., Van Langenhove, T., Theuns, J., Engelborghs, S., Philtjens, S., Vandenbulcke, M., Sleegers, K., Sieben, A., Baumer, V., Maes, G., and 50 others. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum. Mutat. 34: 363-373, 2013. [PubMed: 23111906] [Full Text: https://doi.org/10.1002/humu.22244]
van Es, M. A., Veldink, J. H., Saris, C. G. J., Blauw, H. M., van Vught, P. W. J., Birve, A., Lemmens, R., Schelhaas, H. J., Groen, E. J. N., Huisman, M. H. B., van der Kooi, A. J., de Visser, M., and 42 others. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature Genet. 41: 1083-1087, 2009. [PubMed: 19734901] [Full Text: https://doi.org/10.1038/ng.442]
van Rheenen, W., van Blitterswijk, M., Huisman, M. H. B., Vlam, L., van Doormaal, P. T. C., Seelen, M., Medic, J., Dooijes, D., de Visser, M., van der Kooi, A. J., Raaphorst, J., Schelhaas, H. J., van der Pol, W. L., Veldink, J. H., van den Berg, L. H. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. Neurology 79: 878-882, 2012. [PubMed: 22843265] [Full Text: https://doi.org/10.1212/WNL.0b013e3182661d14]
Vance, C., Al-Chalabi, A., Ruddy, D., Smith, B. N., Hu, X., Sreedharan, J., Siddique, T., Schelhaas, H. J., Kusters, B., Troost, D., Baas, F., de Jong, V., Shaw, C. E. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129: 868-876, 2006. [PubMed: 16495328] [Full Text: https://doi.org/10.1093/brain/awl030]
Xi, Z., van Blitterswijk, M., Zhang, M., McGoldrick, P., McLean, J. R., Yunusova, Y., Knock, E., Moreno, D., Sato, C., McKeever, P. M., Schneider, R., Keith, J., and 12 others. Jump from pre-mutation to pathologic expansion in C9orf72. Am. J. Hum. Genet. 96: 962-970, 2015. [PubMed: 26004200] [Full Text: https://doi.org/10.1016/j.ajhg.2015.04.016]
Xi, Z., Yunusova, Y., van Blitterswijk, M., Dib, S., Ghani, M., Moreno, D., Sato, C., Liang, Y., Singleton, A., Robertson, J., Rademakers, R., Zinman, L., Rogaeva, E. Identical twins with the C9ORF72 repeat expansion are discordant for ALS. Neurology 83: 1476-1478, 2014. [PubMed: 25209579] [Full Text: https://doi.org/10.1212/WNL.0000000000000886]
Xi, Z., Zinman, L., Moreno, D., Schymick, J., Liang, Y., Sato, C., Zheng, Y., Ghani, M., Dib, S., Keith, J., Robertson, J., Rogaeva, E. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet. 92: 981-989, 2013. [PubMed: 23731538] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.017]
Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., and 9 others. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525: 56-61, 2015. [PubMed: 26308891] [Full Text: https://doi.org/10.1038/nature14973]