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FLASH GENE
Symbol C9orf72 contributors: mct - updated : 07-05-2024
HGNC name C9orf72-SMCR8 complex subunit
HGNC id 28337
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a DENN (differentially expressed in normal and neoplastic cells) domain
    • HOMOLOGY
    Homologene
    FAMILY
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • mitochondrial inner-membrane-associated protein
    • basic FUNCTION
  • is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers
  • C9orf72 is a novel RAB1A effector in the regulation of autophagy
  • C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux
  • C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS
  • C9ORF72 regulates trafficking and lysosomal degradation of inflammatory mediators, including toll-like receptors (TLRs) and STING1, to affect inflammatory outputs
  • is a mitochondrial inner-membrane-associated protein regulating cellular energy homeostasis via its critical role in the control of oxidative phosphorylation (OXPHOS)
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • EFHD2 co-aggregates and interacts with known neuropathological proteins, such as MAPT, C9orf72, and LRRK2
  • C9orf72 interacts with RAB1A and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex
  • a C9orf72-containing protein complex and a lysosomal site of action are central to C9orf72 function, providing a foundation for the elucidation of direct physiological targets for C9orf72
  • interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking
  • essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment
  • interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes
  • a stable complex, consisting of C9orf72, SMCR8, and WDR41, has been implicated in regulating membrane trafficking and macroautophagy
  • C9orf72-SMCR8 is a GTPase-activating protein (GAP), and we found that C9orf72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases
  • specifically stabilizes translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1), a crucial factor for the assembly of OXPHOS complex I
  • C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy
  • C9orf72 functions in the nucleus to regulate DNA damage repair
  • DAXX plays a key role in the suppression of basal and stress-inducible expression of C9orf72 via chromatin remodeling and epigenetic modifications of the promoter of the major C9orf72 transcript
  • C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity, and autophagy, and SMCR8 prevents C9orf72 from rapid degradation by the proteasome
  • C9orf72-SMCR8 complex negatively regulates primary ciliogenesis and hedgehog (HH) signaling
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) ALSFTD1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis
    constitutional   amplification    
    in frontotemporal lobar degeneration, with anxiety, agitation and memory impairment and frequent motor neuron disease, with extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts
    constitutional     --low  
    by high methylation level was significantly associated with familial ALS
    constitutional       loss of function
    leads to autoimmunity
    constitutional       loss of function
    promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature and altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities
    Susceptibility to Frontotemporal Lobar Degeneration (FTLD)
    Variant & Polymorphism repeat
  • repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells