Human Molecular Genetics Advance Access originally published online on June 22, 2005
Human Molecular Genetics 2005 14(15):2155-2165; doi:10.1093/hmg/ddi220
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Published by Oxford University Press 2005
The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein
1Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD 20892, USA, 2Genetic Information Research Institute, Mountain View, CA, USA, 3Laboratory of Molecular Carcinogenesis, NIEHS, Research Triangle Park, NC, USA and 4Department of Neurology, Howard Hughes Medical Institute and Beth Israel Deaconess Medical Center, Boston, MA, USA
* To whom correspondence should be addressed. Tel: +1 3014967941; Fax: +1 3014802772; Email: larionov{at}mail.nih.gov
Received April 11, 2005; Revised June 1, 2005; Accepted June 14, 2005
The most common cause of primary autosomal recessive microcephaly (MCPH) appears to be mutations in the ASPM gene which is involved in the regulation of neurogenesis. The predicted gene product contains two putative N-terminal calponin-homology (CH) domains and a block of putative calmodulin-binding IQ domains common in actin binding cytoskeletal and signaling proteins. Previous studies in mouse suggest that ASPM is preferentially expressed in the developing brain. Our analyses reveal that ASPM is widely expressed in fetal and adult tissues and upregulated in malignant cells. Several alternatively spliced variants encoding putative ASPM isoforms with different numbers of IQ motifs were identified. The major ASPM transcript contains 81 IQ domains, most of which are organized into a higher order repeat (HOR) structure. Another prominent spliced form contains an in-frame deletion of exon 18 and encodes 14 IQ domains not organized into a HOR. This variant is conserved in mouse. Other spliced variants lacking both CH domains and a part of the IQ motifs were also detected, suggesting the existence of isoforms with potentially different functions. To elucidate the biochemical function of human ASPM, we developed peptide specific antibodies to the N- and C-termini of ASPM. In a western analysis of proteins from cultured human and mouse cells, the antibodies detected bands with mobilities corresponding to the predicted ASPM isoforms. Immunostaining of cultured human cells with antibodies revealed that ASPM is localized in the spindle poles during mitosis. This finding suggests that MCPH is the consequence of an impairment in mitotic spindle regulation in cortical progenitors due to mutations in ASPM.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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