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ASPM (asp (abnormal spindle) homolog,
microcephaly associated (Drosophila))
Shian-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)
Published in Atlas Database: December 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/ASPMID44463ch1q31.html
DOI: 10.4267/2042/44847
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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 (1q31q32.1) (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).
Identity
Other names: ASP; Calmbp1; DKFZp686N06184;
FLJ10517; FLJ10549; FLJ43117; MCPH5
HGNC (Hugo): ASPM
Location: 1q31.3
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
Genomic diagram of ASPM gene. Exons are represented by boxes on the diagram.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
861
ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
Peng SY, et al.
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.
DNA/RNA
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.
Localisation
ASPM protein, a component of the mitotic spindle,
localizes to the centrosome in interphase and to the
spindle poles from prophase through telophase.
Pseudogene
Function
None.
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 brainspecific 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.
Protein
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.
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%)
Expression
ASPM transcripts were detected in a variety of
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.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
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ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
Peng SY, et al.
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.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
863
ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
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.
Implicated in
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.
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.
References
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S,
Askham JM, Springell K, Mahadevan M, Crow YJ, Markham
AF, Walsh CA, Woods CG. ASPM is a major determinant of
cerebral cortical size. Nat Genet. 2002 Oct;32(2):316-20
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. Protein-truncating mutations in ASPM
cause variable reduction in brain size. Am J Hum Genet. 2003
Nov;73(5):1170-7
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.
Kumar A, Blanton SH, Babu M, Markandaya M, Girimaji SC.
Genetic analysis of primary microcephaly in Indian families:
novel ASPM mutations. Clin Genet. 2004 Oct;66(4):341-8
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. The microcephaly ASPM gene is
expressed in proliferating tissues and encodes for a mitotic
spindle protein. Hum Mol Genet. 2005 Aug 1;14(15):2155-65
Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A,
Woods CG, Walsh CA. ASPM mutations identified in patients
with primary microcephaly and seizures. J Med Genet. 2005
Sep;42(9):725-9
Zhong X, Liu L, Zhao A, Pfeifer GP, Xu X. The abnormal
spindle-like, microcephaly-associated (ASPM) gene encodes a
centrosomal protein. Cell Cycle. 2005 Sep;4(9):1227-9
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. Genetic studies of autosomal
recessive primary microcephaly in 33 Pakistani families: Novel
sequence variants in ASPM gene. Neurogenetics. 2006
May;7(2):105-10
Glioblastoma
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. Analysis of oncogenic
signaling networks in glioblastoma identifies ASPM as a
molecular target. Proc Natl Acad Sci U S A. 2006 Nov
14;103(46):17402-7
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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
Peng SY, et al.
Gul A, Tariq M, Khan MN, Hassan MJ, Ali G, Ahmad W. Novel
protein-truncating mutations in the ASPM gene in families with
autosomal recessive primary microcephaly. J Neurogenet.
2007 Jul-Sep;21(3):153-63
Paramasivam M, Chang YJ, LoTurco JJ. ASPM and citron
kinase co-localize to the midbody ring during cytokinesis. Cell
Cycle. 2007 Jul 1;6(13):1605-12
864
ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila))
Peng SY, et al.
Lin SY, Pan HW, Liu SH, Jeng YM, Hu FC, Peng SY, Lai PL,
Hsu HC. ASPM is a novel marker for vascular invasion, early
recurrence, and poor prognosis of hepatocellular carcinoma.
Clin Cancer Res. 2008 Aug 1;14(15):4814-20
landscape of ASPM mutations in primary microcephaly. J Med
Genet. 2009 Apr;46(4):249-53
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. The molecular
Peng SY, Lin SY, Hsu HC. ASPM (asp (abnormal spindle)
homolog, microcephaly associated (Drosophila)). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(9):861-865.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
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