C9orf72: A Key Genetic Factor in ALS and Frontotemporal Dementia
Explore the C9orf72 gene, its role in neurodegeneration, associated diseases, expression patterns, and mutation mechanisms.
Gene Information Card
| Symbol | C9orf72 |
|---|---|
| Full Name | Chromosome 9 open reading frame 72 |
| Gene Type | Protein coding |
| Chromosomal Location | 9p21.2 |
| NCBI Gene ID | 203228 ncbi.nlm.nih.gov/gene/203228 |
| Ensembl ID | ENSG00000147894 |
| UniProt ID | Q96LT7 |
| OMIM ID | 614260 |
| HGNC ID | 28337 |
| Aliases | ALSFTD, FTDALS, FLJ31684 |
Description
The C9orf72 gene encodes a protein of unknown function, but it is highly conserved and expressed in various tissues. A hexanucleotide repeat expansion (GGGGCC) in the first intron or promoter region is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion leads to both loss-of-function and gain-of-function mechanisms, contributing to neurodegeneration.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Amyotrophic Lateral Sclerosis (ALS) | Hexanucleotide repeat expansion leads to loss of C9orf72 protein and gain of toxic RNA and dipeptide repeat proteins, causing motor neuron degeneration. | OMIM: 614260; ClinVar: pathogenic/likely pathogenic variants |
| Frontotemporal Dementia (FTD) | Same repeat expansion mechanism as ALS, leading to neuronal loss in frontal and temporal lobes. | OMIM: 614260; ClinVar: pathogenic/likely pathogenic variants |
| Frontotemporal Dementia with ALS (FTD-ALS) | Overlap syndrome with both ALS and FTD features, often due to C9orf72 repeat expansion. | OMIM: 614260; ClinVar: pathogenic/likely pathogenic variants |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 20.1 | High |
| Lung | 12.3 | Medium |
| Liver | 8.5 | Medium |
| Kidney | 7.2 | Low |
| Testis | 5.0 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.0 | Neuronal model |
| HeLa (cervical carcinoma) | 10.2 | Epithelial |
| HepG2 (hepatocellular carcinoma) | 8.0 | Liver |
| A549 (lung carcinoma) | 7.5 | Lung |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| GGGGCC repeat expansion (intron 1) | Repeat expansion (typically >30 repeats) | Most common genetic cause of ALS/FTD (up to 40% familial cases) | Loss of function (reduced C9orf72 protein) and gain of function (toxic RNA foci and dipeptide repeat proteins) |
| c.415G>A (p.Ala139Thr) | Missense | Rare | Uncertain significance; possibly pathogenic |
| c.463C>T (p.Arg155*) | Nonsense | Rare | Loss of function; likely pathogenic |
Mutation functional classification
Loss of Function (LOF)
Repeat expansion reduces C9orf72 protein expression, impairing autophagy and endosomal trafficking, contributing to neurodegeneration.
Gain of Function (GOF)
Repeat expansion produces toxic RNA foci that sequester RNA-binding proteins and generate dipeptide repeat proteins (DPRs) via repeat-associated non-ATG (RAN) translation, causing cellular toxicity.
Dominant Negative (DN)
Not clearly established; no evidence of dominant-negative effects for C9orf72 mutations.
View complete mutation data：
Gene Ontology (GO)
| • protein binding | • guanine nucleotide exchange factor activity |
| • autophagy | • endosomal transport |
| • regulation of GTPase activity |
Pathways
• Autophagy
• Endosomal trafficking
• Nucleocytoplasmic transport
• Stress granule dynamics
Protein Summary
The C9orf72 protein is a 481-amino acid protein with a DENN domain, suggesting a role in membrane trafficking and Rab GTPase regulation. It is involved in autophagy and endosomal pathways, critical for neuronal health. Loss of function due to repeat expansion impairs these processes, while gain-of-function toxic species exacerbate neurodegeneration.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| C9orf72 Knockout HEK293 Cell Line | EDJ-KQ5467 | Human | 203228 | Details Get a Quote |
| C9orf72 Knockout HeLa Cell Line | EDJ-KQ17944 | Human | 203228 | Details Get a Quote |
| C9orf72 Knockout A-549 Cell Line | EDJ-KQ28669 | Human | 203228 | Details Get a Quote |
| C9orf72 Knockout HCT 116 Cell Line | EDJ-KQ28670 | Human | 203228 | Details Get a Quote |
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