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ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))

Identity

Other namesASP
Calmbp1
DKFZp686N06184
FLJ10517
FLJ10549
FLJ43117
MCPH5
HGNC (Hugo) ASPM
LocusID (NCBI) 259266
Location 1q31.3
Location_base_pair Starts at 197053257 and ends at 197115824 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Several genes flanking ASPM arranged by an order of centromere to telomere are:
KCNT2 (1q31.3) (potassium channel, subfamily T, member 2)
CFH (1q32) (complement factor H)
CFHR3 (1q32) (complement factor H-related 3)
CFHR1 (1q32) (complement factor H-related 1)
CFHR4 (1q32) (complement factor H-related 4)
CFHR2 (1q31-q32.1) (complement factor H-related 2)
CFHR5 (1q22-q23) (complement factor H-related 5)
F13B (1q31-q32.1) (coagulation factor XIII, B polypeptide)
ASPM (1q31) (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
ZBTB41 (1q31.3) (zinc finger and BTB domain containing 41)
LOC127011 (1q31.3) (similar to ATPase, H+ transporting, lysosomal accessory protein 2)
MRPS21P3 (1q31.2) (mitochondrial ribosomal protein S21 pseudogene 3)
CRB1 (1q31-q32.1) (crumbs homolog 1 (Drosophila))
C1orf218 (1q31.3) (chromosome 1 open reading frame 218)
DENND1B (1q31.3) (DENN/MADD domain containing 1B)
LOC730232 (1q31.3) (similar to eukaryotic translation elongation factor 1 alpha 1)
LOC100129017 (1q31.3) (hypothetical LOC100129017)
C1orf53 (1q31.3) (chromosome 1 open reading frame 53)
LHX9 (1q31-q32) (LIM homeobox 9)
LOC647195 (1q31.3) (hypothetical LOC647195)
NEK7 (1q31.3) (NIMA (never in mitosis gene a)-related kinase 7)

DNA/RNA

 
  Genomic diagram of ASPM gene. Exons are represented by boxes on the diagram.
Description ASPM, maps to NC_000001.10 in human genome, contains 28 exons with a 10,434 base pairs ORF (NCBI GenBank accession number AF509326), spanning a region of 62,568 base pairs at chromosome 1q31.
Transcription ASPM encodes a 10906 bps mRNA, (NM_018136.4), in a telomeric to centromeric orientation and the coding region is from 258 bp to 10961bp (10434 bp). 5' part of exon 1 and 3' part of exon 28 are non-coding. The 28 exons of ASPM mRNA are 554, 144, 1480, 105, 147, 246, 68, 142, 131, 176, 146, 86, 222, 208, 143, 129, 195, 4755, 167, 97, 210, 150, 192, 193, 155, 177, 170, 300 base pairs, respectively.
Pseudogene None.

Protein

 
  ASPM protein contains 2 calponin homology (CH) domains and 81 IQ repeats domain. Total 81 distinct IQ motifs were found at position 1273 to 3243. Numbers indicate the amino acid numbers.
Description The 10434 bps ORF of ASPM mRNA translates a 3477 amino acid protein with a calculated molecular weight of 409.8 kDa. The main ASPM isoform protein, from N-terminal, begins with a microtubule binding domain, followed by two calponin homology (CH) domains, which are possibly responsible for transportation of the ASPM protein to the spindle poles. The third part is IQ (I for isoleucine, Q for glutamine) repeats region which is the calmodulin binding domains. The numbers of IQ repeats are identified up to 81, at position 1273 to 3243. The C-terminal of ASPM is an armadillo-like domain of unknown function.
Expression ASPM transcripts were detected in a variety of human embryo tissues (brain, bladder, colon,heart, liver, lung, skeletal muscle, skin, spleen and stomach), and in adult tissues except for the adult brain, but with much lower amount.
ASPM isoforms were generated by alternative splicing. The brain-specific isoform, main ASPM isoform corresponds to a 3477 amino acid residue protein (410 kDa) containing 81 IQ motifs. Alternatively spliced human ASPM variants code for different numbers of IQ domains. Two major ASPM transcripts with sizes of 10.3 and 5.7 kb were identified in all tissues analyzed. The spliced variants of ASPM with variable sizes were also detected in fetus tissue.
Localisation ASPM protein, a component of the mitotic spindle, localizes to the centrosome in interphase and to the spindle poles from prophase through telophase.
Function ASPM is a spindle pole/centrosome protein, essential for neurogenic mitosis and possibly controlling the fate-switch to asymmetric cell division through the position of the centrosome at mitosis. The brain-specific main ASPM isoform protein appears to be pivotal for the expansion of cerebral cortical size. Other spliced variants contain different IQ domains or lacking both CH domains and a part of the IQ motifs may be potentially with different functions. One of the smaller proteins detected in cell extracts may be the ASPM product required for mitosis by all dividing cells.
Homology According to protein identities compared with Human ASPM:
Pan troglodytes: ASPM; (3443/3477, 99%)
Canis lupus familiaris: ASPM; (2738/3392, 80%)
Bos taurus: ASPM; (2557/3484, 73%)
Mus musculus: Aspm; (1882/2948, 63%)
Rattus norvegicus: Aspm; (1851/2939, 62%)
Danio rerio: aspm; (1390/3554, 39%)

Mutations

 
  Mutation of ASPM in MCPH. According to Nicholas et al. 2009, all reported autosomal recessive primary microcephaly (MCPH) mutations in ASPM have been presented in this table by different kind of mutations, including nonsense mutations, deletions, insertions and mutations in the splicing region. The reference sequence of mutation sites is according to NM_018136.3.

Implicated in

Entity Primary autosomal recessive microcephaly (MCPH)
Note Primary autosomal recessive microcephaly is a neurodevelopment disorder due to the consequence of deficient neurogenesis within the neurogenic epithelium, resulting in congenital microcephaly (reduced brain size) and mental retardation. MCPH is the consequence of impairment in mitotic spindle regulation in cortical progenitors due to mutations in ASPM.
Homozygous mutations in the ASPM gene, located at MCPH5 locus on chromosome 1q31, are the most common cause of MCPH particularly in the Pakistani population. ASPM mutations are restricted to individuals with an MCPH, no defects other than microcephaly are found in patients carrying mutations in this gene. So far, the phenotypic differences in people with different versions of these genes were not found.
  
Entity Hepatocellular carcinoma
Note ASPM, a component of the mitotic spindle, is shown to express in many human malignant cells nearly and all transformed human cell lines, suggesting that ASPM play an important role in cell proliferation in tumorigenesis.
ASPM mRNA was overexpressed in human hepatocellular carcinoma (HCC), but was very low or undetectable in adult liver, and in benign hepatic tumors, such as hepatocellular adenoma and focal nodular hyperplasia. The overexpression of ASPM correlated with higher-grade (grade II-IV), high-stage (stage IIIA-IV which had vascular invasion) and poor prognosis of HCC. In addition, ASPM overexpression is the most important molecular factor associated with ETR (early tumor recurrence) (intrahepatic tumor recurrence and/or distant metastasis within 12 months after HCC tumor resection), and could be used as a molecular marker predicting enhanced invasive/metastatic potential of HCC.
  
Entity Glioblastoma
Note ASPM is essential for normal mitotic spindle function in embryonic neuroblasts, and is recognized as a critical regulator of brain size, it may play a role in promoting neuroblast proliferation. Using gene coexpression module in glioblastoma, ASPM was identified as a key gene of glioblastoma, its overexpression was demonstrated in glioblastoma relative to normal brain. siRNA-mediated ASPM knockdown inhibits neural stem cell self renewal and turn forward neural stem cell differentiation. ASPM knockdown also inhibits cell growth of U87-EGFRvIII cells (glioblastoma cells) and the low passage explant culture from a glioblastoma patient. Those result suggesting that ASPM is a potential molecular target in glioblastoma that resulting in the overexpression of ASPM in glioblastoma.
  
Entity Cancers of the uterus and ovary
Note From high-density oligonucleotide microarrays and using quantitative real-time RT-PCR, ASPM is found more highly expressed in cancers of the uterus and ovary when compared with their normal endometrium counterparts.
  

External links

Nomenclature
HGNC (Hugo)ASPM   19048
Cards
AtlasASPMID44463ch1q31
Entrez_Gene (NCBI)ASPM  259266  asp (abnormal spindle) homolog, microcephaly associated (Drosophila)
GeneCards (Weizmann)ASPM
Ensembl (Hinxton)ENSG00000066279 [Gene_View]  chr1:197053257-197115824 [Contig_View]  ASPM [Vega]
ICGC DataPortalENSG00000066279
cBioPortalASPM
AceView (NCBI)ASPM
Genatlas (Paris)ASPM
WikiGenes259266
SOURCE (Princeton)NM_001206846 NM_018136
Genomic and cartography
GoldenPath (UCSC)ASPM  -  1q31.3   chr1:197053257-197115824 -  1q31   [Description]    (hg19-Feb_2009)
EnsemblASPM - 1q31 [CytoView]
Mapping of homologs : NCBIASPM [Mapview]
OMIM605481   608716   
Gene and transcription
Genbank (Entrez)AF509326 AK001379 AK001380 AK001411 AK095892
RefSeq transcript (Entrez)NM_001206846 NM_018136
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_015867 NT_004487 NW_001838533 NW_004929293
Consensus coding sequences : CCDS (NCBI)ASPM
Cluster EST : UnigeneHs.121028 [ NCBI ]
CGAP (NCI)Hs.121028
Alternative Splicing : Fast-db (Paris)GSHG0002822
Alternative Splicing GalleryENSG00000066279
Gene ExpressionASPM [ NCBI-GEO ]     ASPM [ SEEK ]   ASPM [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8IZT6 (Uniprot)
NextProtQ8IZT6  [Medical]
With graphics : InterProQ8IZT6
Splice isoforms : SwissVarQ8IZT6 (Swissvar)
Domaine pattern : Prosite (Expaxy)CH (PS50021)    IQ (PS50096)   
Domains : Interpro (EBI)ARM-type_fold [organisation]   CAMSAP_CH [organisation]   CH-domain [organisation]   IQ_motif_EF-hand-BS [organisation]   P-loop_NTPase [organisation]  
Related proteins : CluSTrQ8IZT6
Domain families : Pfam (Sanger)CAMSAP_CH (PF11971)    IQ (PF00612)   
Domain families : Pfam (NCBI)pfam11971    pfam00612   
Domain families : Smart (EMBL)CH (SM00033)  IQ (SM00015)  
DMDM Disease mutations259266
Blocks (Seattle)Q8IZT6
Human Protein AtlasENSG00000066279 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ8IZT6
HPRD08384
IPIIPI00743813   IPI00480042   IPI00645386   IPI00745956   
Protein Interaction databases
DIP (DOE-UCLA)Q8IZT6
IntAct (EBI)Q8IZT6
FunCoupENSG00000066279
BioGRIDASPM
InParanoidQ8IZT6
Interologous Interaction database Q8IZT6
IntegromeDBASPM
STRING (EMBL)ASPM
Ontologies - Pathways
Ontology : AmiGOspindle pole  neuron migration  positive regulation of neuroblast proliferation  calmodulin binding  nucleus  cytoplasm  mitotic nuclear division  spermatogenesis  forebrain neuroblast division  midbody  negative regulation of neuron differentiation  negative regulation of asymmetric cell division  oogenesis  developmental growth  maintenance of centrosome location  positive regulation of canonical Wnt signaling pathway  
Ontology : EGO-EBIspindle pole  neuron migration  positive regulation of neuroblast proliferation  calmodulin binding  nucleus  cytoplasm  mitotic nuclear division  spermatogenesis  forebrain neuroblast division  midbody  negative regulation of neuron differentiation  negative regulation of asymmetric cell division  oogenesis  developmental growth  maintenance of centrosome location  positive regulation of canonical Wnt signaling pathway  
Protein Interaction DatabaseASPM
Wikipedia pathwaysASPM
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ASPM
snp3D : Map Gene to Disease259266
SNP (GeneSNP Utah)ASPM
SNP : HGBaseASPM
Genetic variants : HAPMAPASPM
Exome VariantASPM
1000_GenomesASPM 
ICGC programENSG00000066279 
Somatic Mutations in Cancer : COSMICASPM 
CONAN: Copy Number AnalysisASPM 
Mutations and Diseases : HGMDASPM
Genomic VariantsASPM  ASPM [DGVbeta]
dbVarASPM
ClinVarASPM
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM605481    608716   
MedgenASPM
GENETestsASPM
Disease Genetic AssociationASPM
Huge Navigator ASPM [HugePedia]  ASPM [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneASPM
Homology/Alignments : Family Browser (UCSC)ASPM
Phylogenetic Trees/Animal Genes : TreeFamASPM
Chemical/Protein Interactions : CTD259266
Chemical/Pharm GKB GenePA38782
Clinical trialASPM
Cancer Resource (Charite)ENSG00000066279
Other databases
Probes
Litterature
PubMed65 Pubmed reference(s) in Entrez
CoreMineASPM
iHOPASPM
OncoSearchASPM

Bibliography

ASPM is a major determinant of cerebral cortical size.
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG.
Nat Genet. 2002 Oct;32(2):316-20. Epub 2002 Sep 23.
PMID 12355089
 
Protein-truncating mutations in ASPM cause variable reduction in brain size.
Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG.
Am J Hum Genet. 2003 Nov;73(5):1170-7. Epub 2003 Oct 21.
PMID 14574646
 
Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.
Kumar A, Blanton SH, Babu M, Markandaya M, Girimaji SC.
Clin Genet. 2004 Oct;66(4):341-8.
PMID 15355437
 
The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein.
Kouprina N, Pavlicek A, Collins NK, Nakano M, Noskov VN, Ohzeki J, Mochida GH, Risinger JI, Goldsmith P, Gunsior M, Solomon G, Gersch W, Kim JH, Barrett JC, Walsh CA, Jurka J, Masumoto H, Larionov V.
Hum Mol Genet. 2005 Aug 1;14(15):2155-65. Epub 2005 Jun 22.
PMID 15972725
 
ASPM mutations identified in patients with primary microcephaly and seizures.
Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA.
J Med Genet. 2005 Sep;42(9):725-9.
PMID 16141009
 
The abnormal spindle-like, microcephaly-associated (ASPM) gene encodes a centrosomal protein.
Zhong X, Liu L, Zhao A, Pfeifer GP, Xu X.
Cell Cycle. 2005 Sep;4(9):1227-9. Epub 2005 Sep 13.
PMID 16123590
 
Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene.
Gul A, Hassan MJ, Mahmood S, Chen W, Rahmani S, Naseer MI, Dellefave L, Muhammad N, Rafiq MA, Ansar M, Chishti MS, Ali G, Siddique T, Ahmad W.
Neurogenetics. 2006 May;7(2):105-10. Epub 2006 Apr 21.
PMID 16673149
 
Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.
Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS.
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7. Epub 2006 Nov 7.
PMID 17090670
 
Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly.
Gul A, Tariq M, Khan MN, Hassan MJ, Ali G, Ahmad W.
J Neurogenet. 2007 Jul-Sep;21(3):153-63.
PMID 17849285
 
ASPM and citron kinase co-localize to the midbody ring during cytokinesis.
Paramasivam M, Chang YJ, LoTurco JJ.
Cell Cycle. 2007 Jul 1;6(13):1605-12. Epub 2007 Apr 27.
PMID 17534152
 
ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma.
Lin SY, Pan HW, Liu SH, Jeng YM, Hu FC, Peng SY, Lai PL, Hsu HC.
Clin Cancer Res. 2008 Aug 1;14(15):4814-20.
PMID 18676753
 
The molecular landscape of ASPM mutations in primary microcephaly.
Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, Hampshire D, Ahmed M, Bond J, Di Benedetto D, Fichera M, Romano C, Dobyns WB, Woods CG.
J Med Genet. 2009 Apr;46(4):249-53. Epub 2008 Nov 21.
PMID 19028728
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written12-2009Shian-Yang Peng, Shih-Yeh Lin, Hey-Chi Hsu
Department of General Education, National Taipei College of Nursing, Taipei 100, Taiwan, Republic of China (SYP); Graduate Institute of Pathology, College of Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, Republic of China (SYL); Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, Republic of China (HCH)

Citation

This paper should be referenced as such :
Peng, SY ; Lin, SY ; Hsu, HC
ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ASPMID44463ch1q31.html

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indexed on : Wed Jul 30 14:28:52 CEST 2014

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