The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs
Open accessAbstract
Motivation: Fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, also called motor neuron disease, MND) are severe neurodegenerative diseases that show considerable overlap at the clinical and cellular level. The most common single mutation in families with FTD or ALS has recently been mapped to a non-coding repeat expansion in the uncharacterized gene C9ORF72. Although a plausible mechanism for disease is that aberrant C9ORF72 mRNA poisons splicing, it is important to determine the cellular function of C9ORF72, about which nothing is known. Results: Sensitive homology searches showed that C9ORF72 is a full-length distant homologue of proteins related to Differentially Expressed in Normal and Neoplasia (DENN), which is a GDP/GTP exchange factor (GEF) that activates Rab-GTPases. Our results suggest that C9ORF72 is likely to regulate membrane traffic in conjunction with Rab-GTPase switches, and we propose to name the gene and its product DENN-like 72 (DENNL72). Supplementary information: Supplementary data are available at Bioinformatics online. Contact: tim.levine@ucl.ac.uk
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The C9orf72 protein belongs to the DENN family and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling.
“The C9orf72 protein belongs to the DENN (differentially expressed in normal and neoplastic cells) family [143,144] and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling [145].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [143]
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“expressed in normal and neoplastic cells) family [143,144] and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling [145].”
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- Authors
- Levine, T. P., Daniels, R. D., Gatta, A. T., Wong, L. H., & Hayes, M. J.
- Affiliations
- Department of Cell Biology, UCL Institute of Ophthalmology, Bath St, London EC1V 9EL, UK
- University College London (GB)
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-01-16
- Volume
- 29
- Issue
- 4
- Pages
- 499-503
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- PMC
- PMC3570213
- OpenAlex
- W2132191094
- Cited by
- 321
- References
- 36
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 9 · 2021: 23 · 2020: 24 · 2019: 25 · 2018: 30 · 2017: 25 · 2016: 55 · 2015: 42 · 2014: 34 · 2013: 27
- FWCI
- 33.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Bioinformatics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (093445/B/10/Z, 093445)
- Lowe Syndrome Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, frontotemporal dementia, amyotrophic lateral sclerosis, membrane traffic, protein homology, neurodegeneration, gene function
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Humans, Proteins, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Guanine Nucleotide Exchange Factors, Frontotemporal Dementia
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