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MCPH1 (microcephalin 1)

Written2009-03Yulong Liang, Shiaw-Yih Lin, Kaiyi Li
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA (SYL)

(Note : for Links provided by Atlas : click)

Identity

Other namesBRIT1
MCT
HGNC (Hugo) MCPH1
LocusID (NCBI) 79648
Atlas_Id 44370
Location 8p23.1  [Link to chromosome band 8p23]
Location_base_pair Starts at 6264113 and ends at 6304940 bp from pter ( according to hg19-Feb_2009)  [Mapping MCPH1.png]
Local_order According to NCBI Map Viewer, genes flanking MCPH1 in telomere to centromere direction on 8p23.1 are: ANGPT2 (angiopoietin 2); MCPH1 (also BRIT1); AGPAT5 (1-acylglycerol-3-phosphate O-acyltransferase 5 (lysophosphatidic acid acyltransferase, epsilon)); XKR5 (XK, Kell blood group complex subunit-related family, member 5); DEFB1 (defensin, beta 1); DEFA6 (defensin, alpha 6, Paneth cell-specific).
Fusion genes
(updated 2016)
AGPAT5 (8p23.1) / MCPH1 (8p23.1)MCPH1 (8p23.1) / AGPAT5 (8p23.1)MCPH1 (8p23.1) / CSMD1 (8p23.2)
MCPH1 (8p23.1) / EPC2 (2q23.1)MCPH1 (8p23.1) / MCPH1 (8p23.1)MCPH1 (8p23.1) / SSU72 (1p36.33)
TMED3 (15q25.1) / MCPH1 (8p23.1)
Note MCPH1 is one of DNA damage response proteins that interact with other DNA damage and repair proteins and signal transducers, form a DNA damage response protein complex which can be seen through immunofluorescent microscopy, and participate into DNA repair, cell cycle checkpoint control, and eventually maintain genomic integrity. The aberrant expression of MCPH1 is observed in ovarian cancer and breast cancer tissues and cell lines. Thus, functional impairment of MCPH1 may significantly contribute to tumour susceptibility and/or tumour development. In addition, individuals who harbor a germline mutation of MCPH1 gene may be highly susceptible to an autosomal recessive neurological disorder, called primary microcephaly.

DNA/RNA

Description According to Entrez-Gene, MCPH1 gene maps to NC_000008.9 in the region between 6251529 and 6493434 on the plus strand and spans across 241.9 kilo bases. According to GenBank, MCPH1 has 14 exons, the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110, 38, 163, 78, 238, and 5512 bp.
Transcription 8032 bp mRNA (NM_024596.2), 2508 bp open reading frame.

Protein

Note MCPH1 has three BRCA1 carboxyl-terminal (BRCT) domains, so it is regarded as a protein family member involved in DNA damage repair and checkpoint control.
 
  The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA, amino acids).
Description MCPH1 protein contains 835 amino acids with about 110 kDa of the molecular weight. According to MotifScan prediction, MCPH1 has three BRCT domains, one nuclear localization signal motif and the large central IMPDH domain as depicted in the diagram above. The BRCT domains of MCPH1, one in N-terminus (N-BRCT), the other two tandemly arranged in C-terminus (C-BRCTs), specifically bind to the phosphorylated proteins commonly involved in DNA damage response pathways. The N-BRCT is required for centrosomal localization in irradiated cells, and also essential to rescue the premature chromosome condensation in MCPH1-deficient cells. C-BRCTs direct self-oligomerization of MCPH1, and are necessary for ionizing radiation-induced foci formation. The function of IMPDH domain predicted by MotifScan is not clear yet. However, the region (residues 376-485) in the central IMPDH domain (or middle domain), binding with Condension II, participates in homologous recombination.
Expression MCPH1 is ubiquitously expressed in human with the higher levels observed in the brain, testes, pancreas and liver. It is a putative tumor suppressor and the aberrant expression of MCPH1 is correlated with ovarian and breast cancer. This reduced expression of MCPH1 may have been caused by gene deletion detected by high-density array comparative genomic hybridization (CGH).
Localisation Mainly localized in nucleus.
Function MCPH1 function in DNA damage response: MCPH1 can modulate activities of two distinct DNA damage repair networks, the ATM (ataxia telangiectaisia mutated) pathway and the ATR (ATM and Rad3-related) pathway. Upon exposure to DNA damaging reagents, MCPH1 co-localizes with numerous proteins associated with these two signaling pathways including gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR, p-RAD17 and p-RPA34. In the absence of MCPH1, all of these proteins with the exception of gamma-H2AX, fail to localize to sites of DNA damage. The depletion of MCPH1 inhibits the recruitment of phosphorylated ATM to double-stranded DNA break ends, and subsequently impair t phosphorylation of multiple down-stream members of the ATM pathway. MCPH1 deficiency also abolishes the UV-induced phosphorylation of RPA34 and reduces the levels of phosphorylated RAD17, suggesting the roles of MCPH1 in the ATR pathway. Rad51, a homolog of the bacterial RecA, is a central executioner in homologous recombination (HR), catalyzing the invasion of the single stranded DNA in a homologous duplex and facilitating the homology search during the establishment of joint molecules. Lack of MCPH1 can alleviate localization of RAD51 onto the DNA break sites. So MCPH1 is strongly implicated in HR.
Role of BRIT1 in cell cycle control: MCPH1 has been demonstrated to regulate the expression of BRCA1 and Chk1 and required for activation of intra-S and G2/M cell cycle checkpoint after cellular exposure to ionizing radiation. In the absence of MCPH1, BRCA1 and ChK1 expression is significantly reduced and NBS1 fails to be phosphorylated, leading to loss of intra-S and G2/M checkpoint control. Cells derived from a microcephaly patient (MCPH1 defective) maintain a persistent level of CDC25A and reduced level of Cdk1-cyclin B complex, both of which attributes to entry of mitosis. So besides expression control of ChK1 and BRCA1, MCPH1 prevents premature entry into mitosis in an ATR-dependent and ATR-independent manner.
Homology According to NCBI-HomoloGene:
Chimpanzee (Pan troglodytes): MCPH1 (NP_001009010.1, 835 aa)
Dog (Canis familiaris): MCPH1 (NP_001003366.1, 850 aa)
Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986 aa)
Mouse (Mus musculus): MCPH1 (NP_775281.2, 822 aa)
Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1, 422 aa)
Drosophila (Drosophila melanogaster): CG30038 (NP_725086.2, 219 aa)

Mutations

Note Three point mutations in the autosomal recessive mental retardation patients have been described for MCPH1 so far. Two mutations (S25X and 427insA) lead to premature stop condon, and one (T27R) leads to missense mutation in the N-terminal BRCT domain. A non-synonymous SNP (V761A in BRCA1 C-terminus (BRCT) domain) of MCPH1 is significantly associated with cranial volume in Chinese males. In addition, a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, was revealed by Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH). However, the patients with this deletion just showed borderline of mild microcephaly.

Implicated in

Note
Entity Ovarian cancers
Note Aberrations of MCPH1 have been identified in various human cancers.
Disease MCPH1 DNA copy number was substatially decreased in 40% of advanced epithelial ovarian cancer, and its mRNA levels were also dramatically decreased in 63% of ovarian cancer.
  
Entity Breast cancers
Disease MCPH1 mRNA and protein levels was aberrantly reduced in several breast cancer cell lines.
Prognosis Additionally, reduced MCPH1 expression correlated with the duration of the relapse-free intervals and with the occurrence of metastasis in breast cancers. BRIT1 deficiency may contribute to development and aggressive nature of breast tumors.
  
Entity Primary microcephaly
Disease Primary microcephaly is an autosomal recessive disorder, in which there is a marked reduction in brain size. One form of primary microcephaly, MCPH, is caused by mutation in the gene encoding microcephalin 1 (that is, MCPH1). In these patients, the MCPH1-deficient cells show cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for these individuals. As mentioned above, several mutations of MCPH1 have been observed in these patients, including S25X, 427insA, T27R, V761A and 5'-deletion of a large portion encompassing the promoter region and first six exons, especially the later two showing strong correlation with microcephaly.
  
Entity PCC syndrome
Disease Premature chromosome condensation (PCC) syndrome is characterized by premature chromosome condensation in the early G2 phase. This disorder is similar to microcephalin 1, and can also be caused by MCPH1 mutations.
  

Bibliography

Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.
Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Jackson AP, Jeggo PA, O'Driscoll M.
Nat Cell Biol. 2006 Jul;8(7):725-33. Epub 2006 Jun 18.
PMID 16783362
 
BRIT1/MCPH1: a guardian of genome and an enemy of tumors.
Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY.
Cell Cycle. 2006 Nov;5(22):2579-83. Epub 2006 Nov 15.
PMID 17172830
 
SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.
Garshasbi M, Motazacker MM, Kahrizi K, Behjati F, Abedini SS, Nieh SE, Firouzabadi SG, Becker C, Ruschendorf F, Nurnberg P, Tzschach A, Vazifehmand R, Erdogan F, Ullmann R, Lenzner S, Kuss AW, Ropers HH, Najmabadi H.
Hum Genet. 2006 Feb;118(6):708-15. Epub 2005 Nov 26.
PMID 16311745
 
Identification of microcephalin, a protein implicated in determining the size of the human brain.
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG.
Am J Hum Genet. 2002 Jul;71(1):136-42. Epub 2002 Jun 3.
PMID 12046007
 
Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization.
Jeffers LJ, Coull BJ, Stack SJ, Morrison CG.
Oncogene. 2008 Jan 3;27(1):139-44. Epub 2007 Jun 25.
PMID 17599047
 
BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.
Lin SY, Rai R, Li K, Xu ZX, Elledge SJ.
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15105-9. Epub 2005 Oct 10.
PMID 16217032
 
BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.
Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP, Liang J, Mills GB, Meric-Bernstam F, Lin SY.
Cancer Cell. 2006 Aug;10(2):145-57. Epub 2006 Jul 27.
PMID 16872911
 
The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.
Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, Neitzel H.
Hum Mutat. 2005 Nov;26(5):496.
PMID 16211557
 
A common SNP of MCPH1 is associated with cranial volume variation in Chinese population.
Wang JK, Li Y, Su B.
Hum Mol Genet. 2008 May 1;17(9):1329-35. Epub 2008 Jan 19.
PMID 18204051
 
Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair.
Wood JL, Liang Y, Li K, Chen J.
J Biol Chem. 2008 Oct 24;283(43):29586-92. Epub 2008 Aug 21.
PMID 18718915
 
MCPH1 functions in an H2AX-dependent but -independent pathway in response to DNA damage.
Wood JL, Singh N, Mer G, Chen J.
J Biol Chem. 2007 Nov 30;282(48):35416-23. Epub 2007 Oct 9.
PMID 17925396
 
Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.
Xu X, Lee J, Stern DF.
J Biol Chem. 2004 Aug 13;279(33):34091-4. Epub 2004 Jun 25.
PMID 15220350
 
MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis.
Yang SZ, Lin FT, Lin WC.
EMBO Rep. 2008 Sep;9(9):907-15. Epub 2008 Jul 25.
PMID 18660752
 

Citation

This paper should be referenced as such :
Liang, Y ; Lin, SY ; Li, K
MCPH1 (microcephalin 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):243-245.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MCPH1ID44370ch8p23.html


External links

Nomenclature
HGNC (Hugo)MCPH1   6954
Cards
AtlasMCPH1ID44370ch8p23
Entrez_Gene (NCBI)MCPH1  79648  microcephalin 1
AliasesBRIT1; MCT
GeneCards (Weizmann)MCPH1
Ensembl hg19 (Hinxton)ENSG00000147316 [Gene_View]  chr8:6264113-6304940 [Contig_View]  MCPH1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000147316 [Gene_View]  chr8:6264113-6304940 [Contig_View]  MCPH1 [Vega]
ICGC DataPortalENSG00000147316
TCGA cBioPortalMCPH1
AceView (NCBI)MCPH1
Genatlas (Paris)MCPH1
WikiGenes79648
SOURCE (Princeton)MCPH1
Genomic and cartography
GoldenPath hg19 (UCSC)MCPH1  -     chr8:6264113-6304940 +  8p23.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MCPH1  -     8p23.1   [Description]    (hg38-Dec_2013)
EnsemblMCPH1 - 8p23.1 [CytoView hg19]  MCPH1 - 8p23.1 [CytoView hg38]
Mapping of homologs : NCBIMCPH1 [Mapview hg19]  MCPH1 [Mapview hg38]
OMIM251200   607117   
Gene and transcription
Genbank (Entrez)AI379664 AI480294 AI652127 AK022909 AK023946
RefSeq transcript (Entrez)NM_001172574 NM_001172575 NM_001322042 NM_001322043 NM_001322045 NM_024596
RefSeq genomic (Entrez)NC_000008 NC_018919 NG_016619 NT_023736 NW_004929335
Consensus coding sequences : CCDS (NCBI)MCPH1
Cluster EST : UnigeneHs.708770 [ NCBI ]
CGAP (NCI)Hs.708770
Alternative Splicing GalleryENSG00000147316
Gene ExpressionMCPH1 [ NCBI-GEO ]   MCPH1 [ EBI - ARRAY_EXPRESS ]   MCPH1 [ SEEK ]   MCPH1 [ MEM ]
Gene Expression Viewer (FireBrowse)MCPH1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)79648
GTEX Portal (Tissue expression)MCPH1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8NEM0 (Uniprot)
NextProtQ8NEM0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8NEM0
Splice isoforms : SwissVarQ8NEM0 (Swissvar)
PhosPhoSitePlusQ8NEM0
Domaine pattern : Prosite (Expaxy)BRCT (PS50172)   
Domains : Interpro (EBI)BRCT_dom    Microcephalin-like    Microcephalin_mammal   
Domain families : Pfam (Sanger)Microcephalin (PF12258)    PTCB-BRCT (PF12738)   
Domain families : Pfam (NCBI)pfam12258    pfam12738   
Domain families : Smart (EMBL)BRCT (SM00292)  
DMDM Disease mutations79648
Blocks (Seattle)MCPH1
PDB (SRS)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
PDB (PDBSum)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
PDB (IMB)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
PDB (RSDB)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
Structural Biology KnowledgeBase2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
SCOP (Structural Classification of Proteins)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
CATH (Classification of proteins structures)2WT8    3KTF    3PA6    3SHT    3SHV    3SZM    3T1N    3U3Z   
SuperfamilyQ8NEM0
Human Protein AtlasENSG00000147316
Peptide AtlasQ8NEM0
HPRD06174
IPIIPI00002374   IPI00930432   IPI00930120   IPI00956107   IPI00796148   
Protein Interaction databases
DIP (DOE-UCLA)Q8NEM0
IntAct (EBI)Q8NEM0
FunCoupENSG00000147316
BioGRIDMCPH1
STRING (EMBL)MCPH1
ZODIACMCPH1
Ontologies - Pathways
QuickGOQ8NEM0
Ontology : AmiGOprotein binding  nucleoplasm  cytoplasm  microtubule organizing center  cerebral cortex development  identical protein binding  mitotic cell cycle arrest  
Ontology : EGO-EBIprotein binding  nucleoplasm  cytoplasm  microtubule organizing center  cerebral cortex development  identical protein binding  mitotic cell cycle arrest  
REACTOMEQ8NEM0 [protein]
REACTOME PathwaysR-HSA-2299718 Condensation of Prophase Chromosomes [pathway]
NDEx NetworkMCPH1
Atlas of Cancer Signalling NetworkMCPH1
Wikipedia pathwaysMCPH1
Orthology - Evolution
OrthoDB79648
GeneTree (enSembl)ENSG00000147316
Phylogenetic Trees/Animal Genes : TreeFamMCPH1
Homologs : HomoloGeneMCPH1
Homology/Alignments : Family Browser (UCSC)MCPH1
Gene fusions - Rearrangements
Fusion : MitelmanMCPH1/AGPAT5 [8p23.1/8p23.1]  
Fusion : MitelmanMCPH1/CSMD1 [8p23.1/8p23.2]  [t(8;8)(p23;p23)]  
Fusion : COSMICAGPAT5 [8p23.1]  -  MCPH1 [8p23.1]  [fusion_695]  [fusion_696]  
Fusion: TCGAMCPH1 8p23.1 CSMD1 8p23.2 BRCA
Polymorphisms : SNP, variants
NCBI Variation ViewerMCPH1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MCPH1
dbVarMCPH1
ClinVarMCPH1
1000_GenomesMCPH1 
Exome Variant ServerMCPH1
ExAC (Exome Aggregation Consortium)MCPH1 (select the gene name)
Genetic variants : HAPMAP79648
Genomic Variants (DGV)MCPH1 [DGVbeta]
Mutations
ICGC Data PortalMCPH1 
TCGA Data PortalMCPH1 
Broad Tumor PortalMCPH1
OASIS PortalMCPH1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMCPH1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MCPH1
DgiDB (Drug Gene Interaction Database)MCPH1
DoCM (Curated mutations)MCPH1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MCPH1 (select a term)
intoGenMCPH1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)8:6264113-6304940  ENSG00000147316
CONAN: Copy Number AnalysisMCPH1 
Mutations and Diseases : HGMDMCPH1
OMIM251200    607117   
MedgenMCPH1
Genetic Testing Registry MCPH1
NextProtQ8NEM0 [Medical]
TSGene79648
GENETestsMCPH1
Huge Navigator MCPH1 [HugePedia]
snp3D : Map Gene to Disease79648
BioCentury BCIQMCPH1
ClinGenMCPH1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD79648
Chemical/Pharm GKB GenePA30701
Clinical trialMCPH1
Miscellaneous
canSAR (ICR)MCPH1 (select the gene name)
Probes
Litterature
PubMed115 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMCPH1
EVEXMCPH1
GoPubMedMCPH1
iHOPMCPH1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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