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FB2026_01
,
released March 12, 2026
This report describes frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1), which is a subtype of amyotrophic lateral sclerosis. FTDALS1 is associated with the human gene C9orf72, which has an unknown function; however, the causative pathologic agent appears to be an intronic expanded GGGGCC hexanucleotide repeat. No Drosophila ortholog of C9orf72 has been identified.
Multiple UAS constructs of the GGGGCC (G4C2) hexanucleotide repeat have been introduced into flies, including wild-type low copy number repeats, disease-associated expanded repeats, and repeat constructs that produce only RNA or only dipeptide repeats; these constructs are captured as alleles of the synthetic genes Zzzz\GGGGCC, Zzzz\poly-PR, Zzzz\poly-GR, Zzzz\poly-GA. Phenotypes similar to aspects of the human disease are observed; specific dipeptide repeat proteins appear to be neurotoxic in these models. Using constructs containing 80 copies of the relevant 6-nt repeat, (GR)80 and (PR)80, but not (GA)80, have been found to be toxic in neuronal and non-neuronal cells; when co-expressed with (GR)80, (GA)80 reduces the GR-induced toxicity. GGGGCC repeat constructs have been used to investigate the phenomenon of repeat-associated non-AUG translation (RAN), including assessment of genetic modifiers.
Multiple UAS constructs of the human Hsap\C9orf72 have been introduced into flies. A set of constructs that has been designed to test whether the RNA repeat itself is toxic carry a C9orf72 'minigene': exon 1, part of the first intron with synthetic G4C2 repeats of various lengths at the same location as in human, and exon 3. No neurodegenerative phenotypes were observed; intronic 160R formed abundant nuclear G4C2 RNA foci in both neurons and glia, with a few foci outside of the nucleus. These results suggest that nuclear RNA foci could be neutral intermediates or possibly neuroprotective by sequestering RNA repeats in the nucleus and therefore preventing cytoplasmic dipeptide repeat production.
[updated Sep. 2022 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 1; FTDALS1](https://omim.org/entry/105550)
[CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72](https://omim.org/entry/614260)
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, pubmed:16495328). 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, pubmed:23597494). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013, pubmed:23551834; Gomez-Tortosa et al., 2013, pubmed:23284068). [from MIM:105550, 2015.02.12]
FTDALS1 is caused by a heterozygous hexanucleotide repeat expansion (GGGGCC) in a noncoding region of the C9ORF72 gene. Unaffected individuals have 2 to 19 repeats, whereas affected individuals have 250 to 1,600 repeats. However, some individuals can show symptoms with as few as 20 to 22 repeats. (summary by Reddy et al., 2013, pubmed:23423380; Gomez-Tortosa et al., 2013, pubmed:23284068) [from MIM:105550, 2015.02.12]
Induced pluripotent stem cells (iPSCs) from fibroblasts derived from ALS patients with a pathogenic expanded C9ORF72 repeat were reprogrammed 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 interacts with the C9ORF72 GGGGCC repeat; toxic foci in patient cells comprised the expanded pathogenic repeat and sequestered ADARB2. Patient iPSC 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 (Donnelly et al., 2013, pubmed:4139042). [from MIM:105550, 2015.02.12]
A molecular mechanism has been identified 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, the protein nucleolin preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. This suggests 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 (Haeusler et al., 2014, pubmed:24598541). [from MIM:614260, 2015.02.13]
No gene orthologous to human C9orf72 in Drosophila (DIOPT).