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FLASH GENE
Symbol MCPH1 contributors: mct/pgu/shn - updated : 20-06-2013
HGNC name microcephalin 1
HGNC id 6954
Corresponding disease
MCPH1 primary microcephaly 1
Location 8p23.1      Physical location : 6.264.112 - 6.501.140
Synonym name
  • microcephaly, primary autosomal recessive 1
  • microcephalin
  • BRCT-repeat inhibitor of TERT expression 1
  • nuclear mitochondrial deoxynucleotide carrier
  • Synonym symbol(s) MCT, FLJ12847, BRIT1
    DNA
    TYPE functioning gene
    STRUCTURE 237.03 kb     14 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map pter - D8S1099 - D8S1742 - MCPH1 MCPH1 - D8S277 - D8S561 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 - 3154 92.6 835 - 2011 21911480
    7 - 3629 - 562 - 2011 21911480
    8 - 3773 - 610 - 2011 21911480
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly Homo sapiensFetal
    Digestiveliver   moderately Homo sapiensFetal
    Lymphoid/Immunespleen   moderately Homo sapiensFetal
     thymus   lowly Homo sapiensFetal
    Nervousbrain   moderately Homo sapiensFetal
    Respiratorylung   lowly Homo sapiensFetal
    Urinarykidney   moderately Homo sapiensFetal
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal moderately Homo sapiensFetal
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text brain, developing cortex, liver, kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal BRCT domain, required both for coordinating chromosome condensation and brain development
  • three BRCA1 C terminal domains engaged in DNA-protein and protein-protein interactions (BRCT domain), which are known phosphoprotein binding domains implicated in cell cycle control, DNA damage checkpoints, and DNA repair
  • a ring-type zinc finger domain interacts with BAP1
  • two C-terminal BRCT domains required for both oligomerization and E2F1 binding
  • HOMOLOGY
    interspecies homolog to C.elegans MCM6
    ortholog to Mcph1, Mus musculus
    ortholog to MCPH1, pan troglodytes
    ortholog to Mcph1, Rattus norvegicus
    ortholog to mcph1, Danio rerio
    Homologene
    FAMILY
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus
    text
  • tumour suppressor that localizes to the centrosome
  • basic FUNCTION
  • may be involved in cell cycle and apoptosis regulation during neurogenesis
  • involved in the regulation of chromosome condensation and neurodevelopment
  • role in the DNA damage response
  • acts as a regulator of both the intra-S and G2/M checkpoints
  • has a crucial role in the DNA damage response by promoting the expression of Checkpoint kinase 1 (CHEK1) and BRCA1 through the interaction with E2F1 on the promoters of both genes
  • a proximal factor in the DNA damage response pathway
  • a crucial DNA damage regulator in the ATM/ATR pathways potential and acts as a tumor suppressor gene
  • MCPH1 and PCNT regulate mitotic entry
  • via centrosome-associated CHEK1
  • can regulate the telomeric DNA-damage response
  • regulator of ATP-dependent chromatin remodelling complex SWI/SNF in DBA repair
  • essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability
  • controls centrosome numbers after DNA damage, which may indicate a novel tumour suppressive mechanism for microcephalin
  • important regulator of chromosome condensation/decondensation and disruption of the MCPH1-SET interaction might be important for the pathogenesis of primary microcephaly
  • acts as a composite modulator of condensin II to regulate chromosome condensation and shaping
  • required for precise mitotic spindle orientation and regulates the progenitor division mode to maintain brain size
  • crucial gene in the complex cellular machine that is devoted to DNA repair and acts as a regulator of both the intra-S and G2/M checkpoints
  • implicated in various cellular processes including the DNA damage checkpoint, DNA repair, and transcription
  • ensures proper neuroprogenitor expansion and differentiation through its function in the centrosome, and in the DNA damage response
  • CELLULAR PROCESS cell cycle, checkpoint
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • MCPH1E2F1 complex might be important in the maintenance of genomic integrity and correct response to DNA damage
  • forms a complex with condensin II
  • INTERACTION
    DNA chromatin
    RNA
    small molecule
    protein
  • E2F1
  • BRCA2
  • TERF2
  • can recognize phosphorylated CDC27 via its tandem BRCT domains, and interaction between MCPH1 and CDC27 is dependent on the phosphorylation of CDC27
  • SENP8 promoted the interaction between E2F1 and its cofactor MCPH1, which is required for TP73 induction
  • MCPH1 and NCAPG2 proteins interaction control chromosome structure, suggesting that double heterozygosity for null mutations of those two genes of the Condensin II system contribute to mental deficiency with severe microcephaly phenotype
  • BIRC6 acts as a scaffold, bridging the ubiquitin-specific peptidase 8 (USP8) and MCPH1 in a complex to coordinate USP8-catalyzed deubiquitination of MCPH1
  • BIRC6 regulates DNA double-strand break response by promoting USP8 deubiquitination of MCPH1
  • cell & other
    REGULATION
    activated by E2F1
    ASSOCIATED DISORDERS
    corresponding disease(s) MCPH1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in breast cancer
    tumoral     --low  
    in carcinomas
    constitutional        
    lack of MCPH1 or PCNT results in a loss of CHEK1 from centrosomes with subsequently deregulated activation of centrosomal cyclin B-CDK1
    Susceptibility
  • to high cranial volume in Chinese males
  • to autism spectrum disorder (ASD)
  • to Alzheimer disease (AD)
  • MCPH1 polymorphisms are risk of breast cancer
  • predisposition to otitis media
  • Variant & Polymorphism SNP , other
  • significantly associated with high cranial volume in Chinese males
  • changes in copy number of MCPH1 is a susceptibility factor for ASD in the distal short arm of chromosome 8
  • G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • When BRIT1 expression is depleted, cells lose the ionizing radiation (IR)-induced cell cycle arrest and become IR sensitive
  • MCPH1-mutant cell lines show defective G2-M checkpoint arrest and nuclear fragmentation after DNA damage, and contain supernumerary mitotic centrosomes
  • Depletion of BRIT1 increased the accumulation of chromosomal aberrations
  • BRIT1(-/-) mice and mouse embryonic fibroblasts (MEFs) are hypersensitive to gamma-irradiation, BRIT1(-/-) MEFs and T lymphocytes exhibit severe chromatid breaks and reduced RAD51 foci formation after irradiation, and BRIT1(-/-) mice are infertile and meiotic homologous recombination is impaired
  • BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. I
  • Mcph1 disruption in mice results in primary microcephaly
  • MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle
  • Mcph1-deficient (Mcph1(tm1a) (/tm1a) ) mice had mild to moderate hearing impairment (otitis media), small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities
  • deletion of Mcph1 results in a specific reduction of the mouse cerebral cortex at birth, which is persistent through life
  • Ionizing radiation induces a massive apoptosis in the Mcph1-null mouse neocortex and also embryonic lethality