Alternative titles; symbols
HGNC Approved Gene Symbol: ASPM
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:197,084,127-197,146,669 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | Microcephaly 5, primary, autosomal recessive | 608716 | Autosomal recessive | 3 |
The ASPM gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis (Bond et al., 2002).
Bond et al. (2002) adopted a positional cloning strategy to identify the gene mutant in primary microcephaly-5 (MCPH5; 608716), an autosomal recessive form of primary microcephaly (MCPH) that maps to chromosome 1q31. They identified the ASPM gene within a 600-kb region defined by common haplotypes between families, and confirmed the predicted 10,434-bp open reading frame in overlapping segments of cDNA from fetal brain and colon. Northern blot analysis of mRNA from total mouse embryos showed high expression of an Aspm transcript of at least 9.5 kb between embryonic days (E) 11 to 17. In situ hybridization showed preferential expression during cerebral cortical neurogenesis, specifically in the cerebral cortical ventricular zone. Expression was also observed in the proliferative region of the medial and lateral ganglionic eminence and in the ventricular zone of the dorsal diencephalon. Aspm expression was quite intense at E14.5, when there are many progenitor cells in the cortical ventricular zone, but had decreased in intensity by E16.5.
Kouprina et al. (2005) demonstrated that ASPM was widely expressed in fetal and adult human tissues with lower levels in adult tissues. ASPM was upregulated in human ovarian and uterine cancer tissues. The predicted full-length protein contains 3,477 amino acids and has a calculated molecular mass of 410 kD. ASPM contains 2 conserved regions termed ASPM N-proximal (ASNP) repeats, and more than half of the protein consists of 81 C-terminal calmodulin-binding IQ motifs of variable length. Western blot analysis identified several predicted alternatively spliced ASPM variants with fewer IQ motifs. Immunostaining of cultured human cells revealed that ASPM was localized in the spindle poles during mitosis.
Bond et al. (2002) noted that the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice, and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. The results of Bond et al. (2002) and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells. Humans with autosomal recessive primary microcephaly show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Bond et al. (2002) suggested that genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex.
Fish et al. (2006) found that Aspm was concentrated at mitotic spindle poles in mouse neuroepithelial cells, the primary stem and progenitor cells of the mammalian brain. Aspm expression was downregulated during the switch from proliferative to neurogenic cell divisions. Upon RNA interference in telencephalic neuroepithelial cells, Aspm mRNA was reduced, mitotic spindle poles lacked Aspm protein, and the cleavage plane was less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation increased the probability that the cells underwent asymmetric division, i.e., the apical plasma membrane was inherited by only 1 of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a large proportion of neuroepithelial cell progeny was found in the neuronal layer, implying a reduction in the number of neuroepithelial progenitor cells upon Aspm knockdown. Fish et al. (2006) concluded that ASPM is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative division of neuroepithelial cells during brain development.
Horvath et al. (2006) identified ASPM as a highly connected 'hub' gene within a module of mitosis/cell cycle genes that are coexpressed in glioblastoma and breast cancer. They demonstrated ASPM overexpression in glioblastoma compared to normal tissues. Aspm expression was also high in fetal murine neural stem/progenitor cells, and its expression decreased during differentiation. Knockdown of ASPM by small interfering RNA inhibited proliferation in both a human glioblastoma cell line and murine neural stem/progenitor cells.
Bond et al. (2002) determined that the ASPM gene contains 28 exons and spans 62 kb of genomic sequence.
By positional cloning, Bond et al. (2002) identified the ASPM gene within the MCPH5 critical region on 1q31.
In each of 4 consanguineous northern Pakistani families with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found a homozygous truncating mutation in the ASPM gene (605481.0001). Bond et al. (2002) were unable to distinguish phenotypically between the 4 families in which these mutations were found.
Bond et al. (2003) performed a comprehensive mutation screen of the 10.4-kb ASPM gene, identifying 19 mutations in a cohort of 23 consanguineous families. The mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5 to 11 SDs below normal) and of mental retardation (mild to severe), but appeared to be independent of mutation position in the gene.
In affected members of 3 of 9 consanguineous Indian families with primary microcephaly, Kumar et al. (2004) identified 3 different truncating mutations in the ASPM gene (605481.0005-605481.0007). Kumar et al. (2004) stated that 24 mutations in the ASPM gene had been reported in families from Pakistan, Turkey, the Netherlands, Jordan, Saudi Arabia, Yemen, and India (their patients).
Shen et al. (2005) described a mutation (605481.0008) of the ASPM gene in affected members of a family in which epilepsy was associated with primary microcephaly. They suggested that a history of seizures should not preclude the diagnosis of primary microcephaly.
Gul et al. (2006) identified 6 different mutations in the ASPM gene in affected members of 9 unrelated consanguineous Pakistani families with primary microcephaly.
Desir et al. (2008) identified a homozygous mutation in the ASPM gene (605481.0009) in 2 sibs with MCPH5 (608716). Brain MRI showed a simplified gyral pattern.
Nicholas et al. (2009) sequenced the ASPM gene in 3 cohorts of microcephalic children. Pathogenic ASPM mutations were identified in 39% of 99 consanguineous MCPH families, and in 11 (40%) of 27 nonconsanguineous predominantly Caucasian families with a strict diagnosis of MCPH. In contrast, only 3 (7%) of 45 families with a less restricted phenotype, including microcephaly and mental retardation, had an ASPM mutation. Overall, the report identified 27 novel mutations in the ASPM gene, which almost doubled the number of MCPH-associated ASPM mutations. All but 1 of the mutations resulted in premature termination. There were no definitive missense mutations and no genotype/phenotype correlations. Nicholas et al. (2009) concluded that ASPM mutations are the most common cause of strict MCPH.
Passemard et al. (2009) identified homozygous or compound heterozygous mutations in the ASPM gene in 11 (22%) of 52 probands with MCPH. Sixteen novel mutations were identified, and all 18 mutations were truncating or nonsense mutations. The findings of this study expanded the phenotypic spectrum of MCPH5 to include a decrease in OFC with age and mild structural brain imaging anomalies, including simplified gyral pattern, enlarged ventricles, and partial agenesis of the corpus callosum. Two patients had evidence of cortical dysplasia. The anomalies found in these patients suggested that ASPM may be involved not only in mitosis control, but also as an accessory factor in other developmental processes such as migration and cortical layering.
Among 112 consanguineous Iranian families with primary microcephaly, Darvish et al. (2010) found that 13 (14.1%) showed linkage to the MCPH5 locus. However, homozygous mutations in the ASPM gene were found in only 11 of the families. One of the mutations had been previously reported by Nicholas et al. (2009), and 10 mutations were novel, 9 of which were predicted to result in a truncated protein.
Sajid Hussain et al. (2013) found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. Eighteen families showed linkage to the ASPM gene, and pathogenic mutations were found in 17 families. ASPM was the most commonly mutated gene: the homozygous W1326X mutation (605481.0006) was present in 8 families, suggesting a founder effect.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including ASPM, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Mekel-Bobrov et al. (2005) showed that one genetic variant of ASPM in humans arose nearly about 5,800 years ago and has since swept to high frequency under strong positive selection. They sequenced the entire 62.1-kb genomic region of ASPM in samples from 90 ethnically diverse individuals obtained through the Coriell Institute and from a common chimpanzee. Mekel-Bobrov et al. (2005) showed that haplotype 63 had an unusually high frequency of 21%, whereas the other haplotypes ranged from 0.56 to 3.3%. Haplotype 63 differed consistently from the others at multiple polymorphic sites, 2 of which were nonsynonymous, both in exon 18, and are denoted A44871G and C45126A (the numbers indicate genetic positions from the start codon, and letters at the beginning and end indicate ancestral and derived alleles, respectively). These 2 sites reside in a region of open reading frame that was shown to have experienced particularly strong positive selection in the lineage leading to humans (Evans et al., 2004). These findings, especially the remarkably young age of the positively selected variant, suggested that the human brain is still undergoing rapid adaptive evolution.
Currat et al. (2006) commented on the paper by Mekel-Bobrov et al. (2005), stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of ASPM haplotypes without selection. Mekel-Bobrov et al. (2006) responded that the demographic models adopted by Currat et al. (2006) strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which Mekel-Bobrov et al. (2006) had developed their argument for selection.
Yu et al. (2007) did further studies based on the conclusions of Mekel-Bobrov et al. (2005). Yu et al. (2007) compared ASPM empirically to a large number of other loci and found that its variation is not unusual and does not support selection.
In a study of 5 independent population-based samples comprising 2,393 individuals, Mekel-Bobrov et al. (2007) did not find a detectable association between the recent adaptive evolution of either the ASPM or microcephalin (MCPH1; 607117) genes and normal variation in IQ.
Pulvers et al. (2010) developed a line of mice expressing truncated forms of Aspm similar to those causing microcephaly in humans. Heterozygous Aspm mutant mice were indistinguishable from wildtype, but homozygous Aspm mutant mice showed mild microcephaly associated with reduced relative brain weight and cortical thickness. Microcephaly in mutant mice appeared to be due to reduced neural stem cells, since cortical layering appeared normal. In embryonic day-11.5 telencephalon, mutant Aspm localized to spindle poles in metaphase, but it failed to localize to the midbody in telophase. Truncated Aspm proteins also caused massive loss of germ cells, resulting in reduced testis and ovary size accompanied by reduced fertility.
Johnson et al. (2018) used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25 to 40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displayed a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates. These data suggested an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.
In a consanguineous northern Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) identified a homozygous 2-bp deletion in exon 3 of the ASPM gene, 719-720delCT, causing a frameshift leading to premature termination 15 codons downstream.
In a Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found that affected members were homozygous for a 7-bp deletion of the ASPM gene, 1258-1264delTCTCAAG, in exon 3, causing a frameshift leading to premature termination 31 codons downstream.
In a Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found that affected individuals were homozygous for a nonsense mutation resulting from a 7761T-G transversion in exon 18 of the ASPM gene, producing immediate truncation.
In a consanguineous Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found a 1-bp deletion, 9159delA, in exon 21 of the ASPM gene, causing a frameshift leading to premature termination 4 codons downstream.
In 2 sibs with primary microcephaly-5 (MCPH5; 608716), Kumar et al. (2004) identified a homozygous 9178C-T transition in exon 21 of the ASPM gene, resulting in a gln3060-to-ter (Q3060X) substitution. The family was from southern India, and the parents were related.
In a child with primary microcephaly-5 (MCPH5; 608716), born of consanguineous parents from southern India, Kumar et al. (2004) identified a homozygous 3978G-A transition in exon 17 of the ASPM gene, resulting in a trp1326-to-ter (W1326X) substitution.
In 2 sibs with primary microcephaly-5 (MCPH5; 608716), born of consanguineous parents from southern India, Kumar et al. (2004) identified a homozygous 349C-T transition in the ASPM gene, resulting in an arg117-to-ter (R117X) substitution.
In 3 sibs with primary microcephaly-5 (MCPH5; 608716) from a consanguineous family from Saudi Arabia, Shen et al. (2005) identified homozygosity for a 6189T-G transversion in exon 18 of the ASPM gene, resulting in a tyr2063-to-ter (Y2063X) substitution. Two of the sibs had seizures, whereas the other did not.
In 2 sibs, born of consanguineous Moroccan parents, with primary microcephaly-5 (MCPH5; 608716) and simplified gyration pattern on brain MRI, Desir et al. (2008) identified a homozygous 1-bp insertion (4195insA) in exon 18 of the ASPM gene, resulting in a frameshift and premature termination. The unaffected parents were heterozygous for the mutation. MRI in both patients showed that the simplified gyration was more severe in the anterior cortex. The data indicated that at least 1 form of primary microcephaly is allelic to a form of microcephaly with simplified gyral pattern (603802). However, Desir et al. (2008) noted that prenatal and postnatal brain imaging of patients with microcephaly has rarely been reported, suggesting that the 2 disorders may actually represent a phenotypic continuum. The findings also indicated that neuronal depletion of the ASPM gene predominantly affects the anterior cortex.
In 3 of 5 sibs, born of consanguineous Algerian parents, with primary microcephaly-5 (MCPH5; 608716), Saadi et al. (2009) identified compound heterozygosity for 2 mutations in the ASPM gene: a 2389C-T transition in exon 6, resulting in an arg797-to-ter (R797X) substitution, and a 2-bp deletion in exon 18 (7781delAG; 605481.0011), resulting in a frameshift and premature termination. All 3 sibs had low to low-normal birth weight, variable speech impairment, and mental retardation. Brain MRI showed severe hypoplasia of the frontal lobes, moderate posterior parietal atrophy, an anterior orientation of the insula, a thick corpus callosum, and global gyral simplification.
For discussion of the 2-bp deletion in the ASPM gene (7781delAG) that was found in compound heterozygous state in sibs with primary microcephaly-5 (MCPH5; 608716) by Saadi et al. (2009), see 605481.0010.
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