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FLASH GENE
Symbol DISC1 contributors: shn/mct - updated : 30-01-2017
HGNC name disrupted in schizophrenia 1
HGNC id 2888
DNA
TYPE functioning gene
SPECIAL FEATURE overlapping, gene in gene, opposite orientation
text overlapping DISC2
STRUCTURE 414.46 kb     13 Exon(s)
Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site
text structure
  • presence of FOXP2-binding sites in the DISC1 promoter region
  • MAPPING cloned Y linked N status confirmed
    Map cen - D1S225 - D1S251 - DISC1 - D1S3462 - D1S2709 - qter
    RNA
    TRANSCRIPTS type messenger
    text
  • intergenic splicing with TSNAX ; alternate transcriptional splice variants encode different isoforms
  • produces more than 50 splice variants in the brain (Wertheim 2009)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 splicing 7003 95 832 brain 2009 19805229
  • also called transcript variant Lv
  • alternate in-frame splice site in the 3' coding region
  • 3 splicing 2636 - 369 - 2009 19805229
  • also called transcript variant Es
  • has multiple differences in the coding region, compared to variant L, including an alternate exon which results in an early stop codon, known as "extremely short" isoform (Es)
  • 10 splicing 2230 75 678 brain 2009 19805229
  • also called transcript variant S
  • multiple difference in the coding region compared to variant L
  • 13 splicing 7069 95 854 brain 2009 19805229
    the longest transcript
    14 splicing 7165 - 886 - -
    also called transcript variant a
    13 splicing 3018 - 803 - -
    also called transcript variant b
    11 splicing 2676 - 755 - -
    also called transcript variant c
    13 splicing 6703 - 732 - -
    also called transcript variant d
    11 splicing 2957 - 695 - -
    also called transcript variant e
    11 splicing 2710 - 681 - -
    also called transcript variant j
    11 splicing 2761 - 662 - -
    also called transcript variant g
    8 splicing 2658 - 579 - -
    also called transcript variant h
    7 splicing 2363 - 559 - -
    also called transcript variant i
    8 splicing 2671 - 559 - -
    also called transcript variant j
    7 splicing 2603 - 551 - -
    also called transcript variant k
    7 splicing 2279 - 547 - -
    also called transcript variant l
    4 splicing 2832 - 429 - -
    also called transcript variant m
    4 splicing 1864 - 423 - -
    also called transcript variant n
    4 splicing 2783 - 387 - -
    also called transcript variant o
    4 splicing 2706 - 387 - -
    also called transcript variant p
    3 splicing 1707 - 375 - -
    also called transcript variant q
    3 splicing 1794 - 356 - -
    also called transcript variant r
    7 splicing 1553 - 201 - -
    also called transcript variant t
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveliver   lowly
    Endocrinepancreas   moderately
    Nervousbrainforebraincerebral lobeoccipital lobehighly
     brainhindbrainmedulla oblongata highly
     brainforebraincerebral lobefrontal lobehighly
     brainforebraincerebral cortex highly
     brainhindbraincerebellum highly
     braindiencephalonthalamus highly
     brainmidbrainsubstantia nigra highly
     brainlimbic systemhippocampus highly
     braindiencephalonamygdala highly
     brainbasal nucleicorpus callosum highly
     brainbasal nucleicaudate nucleus highly
     brainforebraincerebral lobetemporal lobehighly
     spinal cord   highly
    Reproductivefemale systemplacenta  highly
    Respiratorylung   lowly
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal lowly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text strongly expressed in the hippocampus from its early development through adulthood (
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a globular N terminus domain
  • helical C terminal domain potentially forming a coiled-coil (critical for the subcellular targeting of DISC1) by interaction with other undefined proteins
  • three leucine zipper domains
  • two UVR-like domains, mediating potentially its self-association
  • two nuclear localization signal
  • region 446-533 AAs is the kendrin-binding region
  • C-terminal NDEL1 binding domain, narrowed down to a small portion of exon 13, corresponding to amino acids 802-835, indispensable for the interaction with kendrin and also required for the centrosomal targeting of DISC1 , which harbors also a dimerization domain and is considered necessary for neuronal migration complex assembly (PMID;
  • secondary structure
  • two alpha-helices connected by a loop, rather than being a single long alpha-helix as might occur in a coiled coil
  • HOMOLOGY
    interspecies ortholog to Disc1, Mus musculus
    ortholog to DISC1, Pan troglodytes
    ortholog to disc1, Danio rerio
    ortholog to Disc1, Rattus norvegicus
    Homologene
    FAMILY
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus
    text
  • centriolar
  • subcellular fractionation showed that the 95- to 100-kD isoform of DISC1 was enriched in the cytoplasm, whereas the 75- to 85-kD isoform was present in both the nucleus and cytoplasm
  • localizes to the centrosome by binding to kendrin (PCNT) (connected to its role in neuronal migration, since the centrosome is believed to aid nuclear movement (nucleokinesis) as neurons move to its final destination in the cortex)
  • basic FUNCTION
  • involved in the regulation of microtubule dynamics
  • DISC1-kendrin interaction plays a key role in the microtubule dynamics (
  • is a multifunctional protein whose truncation may contribute to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture, and/or neuronal migration
  • essential for maintaining the motor complex at the centrosome
  • involved in cortical development through its interaction with other proteins
  • crucial role of NDEL1, together with DISC1 in cortical layer formation
  • sequestering PDE4B in resting cells and releasing it in an activated state in response to elevated cAMP
  • playing a role in neuronal outgrowth, possibly through reported interactions with the molecules NDEL1 and FEZ1
  • key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and acting as a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis
  • acting as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, PAFAH1B1, and YWHAE
  • required for NTF3-induced axon elongation and ERK activation at the distal part of axons by recruiting GRB2 to axonal tips
  • regulates the localization of NDEL1/PAFAH1B1/YWHAE complex into the axons as a cargo receptor for axon elongation
  • acting as an assembly scaffold for NDE1/NDEL1/LIS1/dynein complex modulated by cAMP levels via Protein Kinase A and PDE4
  • highly expressed in neural progenitor cells and required for their proliferation involving regulation of the b-catenin/GSK3b pathway
  • stabilizes b-catenin by inhibiting GSK3b activity through a direct interaction
  • regulate neuronal progenitor proliferation by modulating GSK3B-catenin signalling
  • involved in neurite outgrowth, neuronal migration, integration of newborn neurons, and cAMP signaling
  • participates in the Wnt signaling pathway and in Wnt-mediated cell proliferation
  • essential for neural progenitor proliferation in embryonic brains and in the dentate gyrus of adult brains through its ability to fine-tune GSK3b activity
  • role in neuronal migration in the developing and adult hippocampus (
  • having a role in glial function (
  • regulates the recruitment of pericentriolar material 1 (PCM1) to the centrosome (
  • critical for the stability of Mitofilin (IMMT) (
  • plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin (IMMT)(
  • lays roles for intrinsic mitochondrial functions through regulation of the stability of Mitofilin, a mitochondrial interacting partner (
  • dual role in corticogenesis and indicate that phosphorylation of DISC1 activates a key developmental switch (
  • DISC1 functional activity is potentially downstream of NMDA receptor signaling
  • YWHAE and DISC1, two schizophrenia susceptibility factors have been implicated in the regulation of spine density
  • is likely necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE)
  • FOXP2, DISC1 and the NRXN family in a molecular network that, when altered, confers risk for neurodevelopmental conditions in which various aspects of linguistic and cognitive function are disturbed, possibly via aberrant synaptic function
  • direct presynaptic function for the schizophrenia-associated gene, DISC1
  • intracellular scaffolding molecule thought to act an important hub for protein interactions involved in signalling for neural cell differentiation and function
  • multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with PDE4
  • DISC1 and CHL1 may engage in physical and functional interaction in neural development
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS behavioral , development , nervous system
    PATHWAY
    metabolism
    signaling
    a component
  • formed a ternary complex with GRB2 and kinesin heavy chain KIF5A of Kinesin-1
  • DISC1-PDE4B complexes are therefore likely to be involved in molecular mechanisms underlying psychiatric illness
  • forms octamers via dimers as building blocks and directly interacts with tetramers of NDEL1
  • DTNBP1 and DISC1 form a physiologically functional complex that is essential for normal neurite outgrowth
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • DISC2, MIPT3, MAP1A, ATF4, ATF5, SPTBN4 and ACTN2
  • MAP1A, MIPT3, ATF4/5 and NUDEL (
  • elongation protein zeta-1, FEZ1 (
  • kendrin (PCNT) (
  • PDE4B and altering phosphodiesterase activity
  • cooperates with its binding partner NDEL1 in regulating adult neurogenesis (interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth)
  • GRB2
  • UCR2 domain of phosphodiesterase 4B
  • NDE1/NDEL1/LIS1/dynein complex (
  • glycogen synthase kinase 3 beta, GSK3B (
  • DISC1-interacting protein, CCDC141
  • interaction between DISC1 and TNS2
  • FOXP2 might functionally regulate DISC1 expression
  • DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons
  • DISC1 binds ITPR1 mRNA with ZNF385A, thereby regulating its dendritic transport for synaptic plasticity
  • DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins RHOT1, RHOT2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins)
  • DISC1 in association with SNPH is a component of a modulatory complex that determines mitochondrial anchoring in response to neuronal activation
  • cell & other
    REGULATION
    repressed by FOXP2 (transcriptionally repressed by FOXP2, a transcription factor that is mutated in individuals with a rare autosomal dominant form of DVD (developmental verbal dyspraxia)
    Other may be regulated by DISC2
    regulated at the synapse by NMDA receptor transmission
    ASSOCIATED DISORDERS
    corresponding disease(s) SCZD12
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
        translocation    
    disrupted in schizophrenia with a balanced translocation t(1;11) (q42.1;q14.3)
    constitutional       loss of function
    facilitates ubiquitination of IMMT and presumably, proteasome-mediated degradation of Mitofilin
    constitutional     --low  
    synaptic reduction of DISC1 and YWHAE is developmentally correlated with the age-dependent decrease in striatal spine density
    tumoral fusion      
    chimeric TSNAX-DISC1 occurred significantly upregulated in multiple endometrial carcinoma samples
    Susceptibility susceptibility to psychiatric illnesses:
  • to schizophrenia
  • to bipolar spectrum disorder
  • to major depressive disorder (MDD)
  • to autism spectrum disorders
  • to Attention-deficit/hyperactivity disorder (ADHD)
  • Variant & Polymorphism SNP
  • SNP HEP3 significantly undertransmitted by affected female
  • over-representation of the exon 9 missense allele Phe607 in schizoaffective disorder
  • S704C associated with schizophrenia and an increased risk of developing MDD
  • deleted in autism spectrum disorders
  • short transcripts, are more highly expressed during fetal development than later in life, and are more highly expressed in the brains of patients with schizophrenia than in control brains, and associated with genetic variations in the DISC1 gene
  • schizophrenia risk variant S704C affects the formation of octamers of DISC1 and exhibits higher-order self-oligomerization
  • DISC1 variation is potentially involved in several common neurodevelopmental disorders including ADHD
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • transgenic mouse model expressing a dominant-negative truncated form of human DISC1 displayed several behavioral abnormalities, including hyperactivity, disturbances in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit
  • inducible and reversible transgenic system of mutant C-terminal DISC1 in mice resulted in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, decreased hippocampal synaptic transmission, depressive-like traits, abnormal spatial working memory, and reduced sociability
  • mice carrying a deletion in the mouse Disc1 gene had alterations in the organization of neurons of the dentate gyrus, a deficit in short-term plasticity in the hippocampus and a selective impairment in working memory
  • point mutations in exon 2 of mouse DISC1 lead to the manifestation of schizophrenia- or depression-like behaviors
  • mouse mutant containing two stop codons shows abnormal morphology of newborn neurons and reduced synapse number accompanied by a working memory deficit
  • GSK3b inhibition can rescue the defect in neural progenitor cell proliferation induced by DISC1 suppression in mouse embryonic cortex and adult dentate gyrus