Primary microcephaly: do all roads lead to Rome?
Authors: Gemma K. Thornton, C. Geoffrey Woods
Journal: Trends in Genetics (2009)

The relatively large brain and expanded cerebral cortex of humans is unusual in the animal kingdom and is thought to have promoted our adaptability and success as a species. One approach for investigating neurogenesis is the study of autosomal recessive primary microcephaly (MCPH), in which prenatal brain growth is significantly reduced without an effect on brain structure. To date, eight MCPH loci and five genes have been identified. Unexpectedly, all MCPH proteins are ubiquitous and localise to centrosomes for at least part of the cell cycle. Here, we focus on recent functional studies of MCPH proteins that reveal the centrosome as a final integration point for many regulatory pathways affecting prenatal neurogenesis in mammals. The relatively large brain and expanded cerebral cortex of humans is unusual in the animal kingdom and is thought to have promoted our adaptability and success as a species. One approach for investigating neurogenesis is the study of autosomal recessive primary microcephaly (MCPH), in which prenatal brain growth is significantly reduced without an effect on brain structure. To date, eight MCPH loci and five genes have been identified. Unexpectedly, all MCPH proteins are ubiquitous and localise to centrosomes for at least part of the cell cycle. Here, we focus on recent functional studies of MCPH proteins that reveal the centrosome as a final integration point for many regulatory pathways affecting prenatal neurogenesis in mammals. The initial definition of autosomal recessive primary microcephaly (MCPH; see Glossary) has proved useful to both clinicians and researchers: an individual with a small but structurally normal brain, a mild-to-moderate mental retardation but otherwise normal in appearance, health and neurological functioning [1Cox J. et al.What primary microcephaly can tell us about brain growth.Trends Mol. Med. 2006; 12: 358-366Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 2Nicholas A.K. et al.The molecular landscape of ASPM mutations in primary microcephaly.J. Med. Genet. 2009; 46: 249-253Crossref PubMed Scopus (78) Google Scholar]. As such, MCPH can be considered a 'model' disease to find genes that have essential and non-redundant functions in prenatal neurogenesis. The incidence is ∼1 in 10 000 in consanguineous populations, less in non-consanguineous populations. The cerebral cortex is particularly reduced in size in this disorder, leading to an apparently 'simplified gyral pattern' as mantle thickness is preserved but surface area is reduced [3Barkovich J.A. et al.A developmental classification of malformations of the brainstem.Ann. Neurol. 1997; 62: 625-639Crossref Scopus (68) Google Scholar, 4Desir J. et al.Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.Am. J. Med. Genet. A. 2008; 146A: 1439-1443Crossref PubMed Scopus (61) Google Scholar]. Magnetic resonance imaging studies of an affected family having prenatal diagnosis have shown the frontal lobes of the cerebral cortex to be particularly affected [4Desir J. et al.Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.Am. J. Med. Genet. A. 2008; 146A: 1439-1443Crossref PubMed Scopus (61) Google Scholar, 5Saadi A. et al.Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.Eur. J. Med. Genet. 2008; 52: 180-184Crossref Scopus (20) Google Scholar]. There are at least eight MCPH loci, and the genes underlying five of these have been identified (Table 1). The most recent MCPH gene to be identified was the MCPH7 gene SIL/STIL, from four consanguineous Indian families [6Kumar A. et al.Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.Am. J. Hum. Genet. 2009; 84: 286-290Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar]. Mutations in SIL are a rare cause of MCPH, as are mutations in the genes encoding cyclin-dependent kinase 5 regulatory associated protein 2 (CDK5RAP2) and centromere protein J (CENPJ), as no further cases were found in a cohort of 100 Pakistani MCPH families [6Kumar A. et al.Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.Am. J. Hum. Genet. 2009; 84: 286-290Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar]. Mutations in the abnormal spindle-like microcephaly associated gene (ASPM) cause 50% of MCPH, irrespective of ethnic background [2Nicholas A.K. et al.The molecular landscape of ASPM mutations in primary microcephaly.J. Med. Genet. 2009; 46: 249-253Crossref PubMed Scopus (78) Google Scholar, 7Gul A. et al.Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene.Neurogenetics. 2006; 7: 105-110Crossref PubMed Scopus (50) Google Scholar, 8Gul A. et al.Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly.J. Neurogenet. 2007; 21: 153-163Crossref PubMed Scopus (24) Google Scholar, 9Muhammad F. et al.Compound heterozygous ASPM mutations in Pakistani MCPH families.Am. J. Med. Genet. A. 2009; 149A: 926-930Crossref PubMed Scopus (29) Google Scholar], whereas MCPH2 mutations account for 10% of cases. Although the MCPH2 locus was discovered in 1999, the gene has eluded discovery so far despite extensive sequencing of the locus, suggesting that the mutational mechanism is unusual and not detectable by conventional exonic sequencing. A third of MCPH cases have not been linked to known loci, so further genes await discovery. All the MCPH proteins identified are ubiquitously expressed and have a centrosomal association for at least part of the cell cycle; suggesting knowledge of a centrosomal association might provide guidance in the selection of candidate genes.Table 1MCPH genes, proteins, localisations and functionsaThe HGNC name is highlighted in bold for each gene, although the most common alternatives are also given.LocusChromosome locationGeneProteinCellular localisationFunctionMCPH18p23MCPH1/MICROCEPHALIN/BRIT1 (BRCT inhibitor of telomerase I)Microcephalin/BRIT1Nucleus/chromatin; centrosomeDNA damage repair; chromosome condensation; transcriptional regulation of DNA damage genesMCPH219q13.12–q13.2Not identifiedUnknownNot knownUnknownMCPH39q33.2CDK5RAP2/CEP215 (centrosomal protein 215)CDK5RAP2/Cep215Centrosome throughout cell cycle; midbody at cytokinesisPredicted role in regulating microtubule dynamics; PCM recruitment and stabilisation; centrosome maturation and cohesionMCPH415q15–q21Not identifiedUnknownNot knownUnknownMCPH51q31.3ASPMASPMPericentrosomal at mitotic spindle poles; midbody at cytokinesis; cytoplasmic at interphaseSpindle pole organisation and orientationMCPH613q12.12CENPJ/CPAP (centrosome protein 4.1 associated protein)CENPJ/CPAPCentrosome throughout cell cycle; midbody at cytokinesisCentriole biogenesis and length; microtubule dynamicsMCPH71p33STIL/SILSIL/STILPericentrosomal at mitotic spindle polesSpindle organisation; Hh/Shh signallinga The HGNC name is highlighted in bold for each gene, although the most common alternatives are also given. Open table in a new tab Almost all mutations that cause MCPH introduce a premature stop codon, predicted to cause nonsense-mediated decay [2Nicholas A.K. et al.The molecular landscape of ASPM mutations in primary microcephaly.J. Med. Genet. 2009; 46: 249-253Crossref PubMed Scopus (78) Google Scholar, 9Muhammad F. et al.Compound heterozygous ASPM mutations in Pakistani MCPH families.Am. J. Med. Genet. A. 2009; 149A: 926-930Crossref PubMed Scopus (29) Google Scholar]. Whether these lead to functional nulls (no protein produced), or a significant reduction in protein levels is as yet undetermined. However, two missense mutations have been reported; one in CENPJ and one in ASPM, but their clinical significance remains unclear in lieu of functional studies [7Gul A. et al.Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene.Neurogenetics. 2006; 7: 105-110Crossref PubMed Scopus (50) Google Scholar]. This is particularly important when interpreting ASPM mutations as it is a large gene containing many, often rare, non-synonymous SNPs [2Nicholas A.K. et al.The molecular landscape of ASPM mutations in primary microcephaly.J. Med. Genet. 2009; 46: 249-253Crossref PubMed Scopus (78) Google Scholar]. Therefore, any missense mutation in ASPM should be regarded as non-pathogenic until proven otherwise [2Nicholas A.K. et al.The molecular landscape of ASPM mutations in primary microcephaly.J. Med. Genet. 2009; 46: 249-253Crossref PubMed Scopus (78) Google Scholar]. Microcephalic osteodysplastic primordial dwarfism - type Majewski II (MOPD-II) has an interesting phenotypic overlap with MCPH and Seckel syndrome. A disorder characterised by prenatal onset proportionate short stature, primary microcephaly and a distinctive facies associated with severe developmental delay. MOPD-II results in a marked microcephaly of similar severity to MCPH but with proportionate short stature, which is not seen in MCPH (there is some speculation that Homo floresiensis is a case of MOPD-II; Box 1). In further contrast to MCPH, individuals affected with MOPD-II have cognitive abilities within the normal range. The MOPD-II gene has recently been identified as pericentrin (PCNT) [10Willems M. et al.Molecular analysis of Pericentrin gene (PCNT) in a series of 24 Seckel/MOPD II families.J. Med. Genet. 2009; (DOI:jmg2009.067298v1)PubMed Google Scholar, 11Rauch A. et al.Mutations in the Pericentrin (PCNT) gene cause primordial dwarfism.Science. 2008; 319: 816-819Crossref PubMed Scopus (323) Google Scholar, 12Griffith E. et al.Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling.Nat. Genet. 2008; 40: 232-236Crossref PubMed Scopus (254) Google Scholar], which encodes a key centrosomal protein, a further indicator that centrosomal proteins and/or centrosomes act as key organisers of early neurogenesis.Box 1MCPH, evolution and the link with Homo floresiensisThere has been a clear increase in relative brain size from monkeys to apes to humans. In just 3–5 million years the human brain increased threefold in size compared with that of our closest primate relatives. This has led to a search for the genes (and the changes within those genes) responsible for this expansion. The MCPH genes were obvious candidates as mutations affect brain size exclusively, and evidence of positive Darwinian selection was found in the monkey–primate–human evolutionary tree for MCPH1, 3, 5 and 6 [1Cox J. et al.What primary microcephaly can tell us about brain growth.Trends Mol. Med. 2006; 12: 358-366Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 57Evans P.D. et al.Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.Gene. 2006; 375: 75-79Crossref PubMed Scopus (74) Google Scholar]. This evidence was gathered by comparing the rate of DNA base changes that do not affect protein sequence (synonymous) with those that do change an amino acid (non-synonymous) both within and between species over a defined time period. Non-synonymous changes can alter protein function. This alteration can be beneficial and subsequently either 'selected for', neutral, or deleterious and 'selected against'.Taking this approach further, when whole brain, cerebellum and cerebral cortex were analysed separately in primates, ASPM positive selection correlated only with cerebral cortex size, and appeared to be due to changes in only 16 out of the 3477 amino acids constituting ASPM [58Ali F. Meier R. Positive selection in ASPM Is correlated with cerebral cortex evolution across primates but not with whole-brain size.Mol. Biol. Evol. 2008; 25: 2247-2250Crossref PubMed Scopus (29) Google Scholar]. Controversially, it was claimed that ASPM and MCPH1 were still undergoing evolutionary change in modern humans [59Mekel-Bobrov N. et al.Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.Science. 2005; 309: 1720-1722Crossref PubMed Scopus (337) Google Scholar, 60Evans P.D. et al.Microcephalin, a gene regulating brain size, continues to evolve adaptively in Humans.Science. 2005; 309: 1717-1720Crossref PubMed Scopus (368) Google Scholar, 61Mekel-Bobrov N. et al.The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.Hum. Mol. Genet. 2007; 16: 600-608Crossref PubMed Scopus (71) Google Scholar, 62Dobson-Stone C. et al.Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort.NeuroImage. 2007; 37: 394-400Crossref PubMed Scopus (24) Google Scholar]. Remarkably, the 'selected' changes were not altering either brain size or intelligence and it was hypothesized that sperm number or function was instead being affected (although ASPM MCPH males have fathered children). However, other groups have disputed the validity of these findings, as they could not be replicated, instead suggesting that the high variability observed in ASPM renders such analysis inaccurate [63Currat M. et al.Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'Microcephalin, a gene regulating brain size, continues to evolve adaptively in Humans'.Science. 2006; 313: 172Crossref PubMed Scopus (105) Google Scholar, 64Yu F. et al.Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens'.Science. 2007; 316: 370Crossref PubMed Scopus (41) Google Scholar]. Another study claimed that a MCPH1 haplotype, present in 70% of modern humans, originated from another hominid species [65Evans P.D. et al.Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 18178-18183Crossref PubMed Scopus (117) Google Scholar]. Such nucleotide-based analyses of MCPH are highly complex, however, and await careful validation by functional studies.Finally, the remains of a dwarfed microcephalic hominid found on the Flores Islands, Homo floresiensis, was speculated to be a case of either MOPD-II or MCPH [11Rauch A. et al.Mutations in the Pericentrin (PCNT) gene cause primordial dwarfism.Science. 2008; 319: 816-819Crossref PubMed Scopus (323) Google Scholar, 66Martin R.D. et al.Flores hominid: new species or microcephalic dwarf?.Anat. Rec. A: Discover. Mol. Cell. Evol. Biol. 2006; 288A: 1123-1145Crossref Scopus (86) Google Scholar] rather than a new hominid species. Further analysis has now supported the original theory that H. floresiensis was a separate hominid species that did exist, but became extinct [67Gordon A.D. et al.The Homo floresiensis cranium (LB1): size, scaling, and early Homo affinities.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4650-4655Crossref PubMed Scopus (64) Google Scholar]. Despite the need for functional analyses of these changes, these reports provide exciting speculations about the development of humans as a species. As the Neanderthal genome nears completion, all the DNA changes separating modern humans from their closest hominid relative, who became extinct 30 000 years ago, will soon be known [68Dalton R. Neanderthal genome to be unveiled.Nature. 2009; 457: 645Crossref PubMed Scopus (2) Google Scholar]. There has been a clear increase in relative brain size from monkeys to apes to humans. In just 3–5 million years the human brain increased threefold in size compared with that of our closest primate relatives. This has led to a search for the genes (and the changes within those genes) responsible for this expansion. The MCPH genes were obvious candidates as mutations affect brain size exclusively, and evidence of positive Darwinian selection was found in the monkey–primate–human evolutionary tree for MCPH1, 3, 5 and 6 [1Cox J. et al.What primary microcephaly can tell us about brain growth.Trends Mol. Med. 2006; 12: 358-366Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 57Evans P.D. et al.Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ.Gene. 2006; 375: 75-79Crossref PubMed Scopus (74) Google Scholar]. This evidence was gathered by comparing the rate of DNA base changes that do not affect protein sequence (synonymous) with those that do change an amino acid (non-synonymous) both within and between species over a defined time period. Non-synonymous changes can alter protein function. This alteration can be beneficial and subsequently either 'selected for', neutral, or deleterious and 'selected against'. Taking this approach further, when whole brain, cerebellum and cerebral cortex were analysed separately in primates, ASPM positive selection correlated only with cerebral cortex size, and appeared to be due to changes in only 16 out of the 3477 amino acids constituting ASPM [58Ali F. Meier R. Positive selection in ASPM Is correlated with cerebral cortex evolution across primates but not with whole-brain size.Mol. Biol. Evol. 2008; 25: 2247-2250Crossref PubMed Scopus (29) Google Scholar]. Controversially, it was claimed that ASPM and MCPH1 were still undergoing evolutionary change in modern humans [59Mekel-Bobrov N. et al.Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.Science. 2005; 309: 1720-1722Crossref PubMed Scopus (337) Google Scholar, 60Evans P.D. et al.Microcephalin, a gene regulating brain size, continues to evolve adaptively in Humans.Science. 2005; 309: 1717-1720Crossref PubMed Scopus (368) Google Scholar, 61Mekel-Bobrov N. et al.The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.Hum. Mol. Genet. 2007; 16: 600-608Crossref PubMed Scopus (71) Google Scholar, 62Dobson-Stone C. et al.Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort.NeuroImage. 2007; 37: 394-400Crossref PubMed Scopus (24) Google Scholar]. Remarkably, the 'selected' changes were not altering either brain size or intelligence and it was hypothesized that sperm number or function was instead being affected (although ASPM MCPH males have fathered children). However, other groups have disputed the validity of these findings, as they could not be replicated, instead suggesting that the high variability observed in ASPM renders such analysis inaccurate [63Currat M. et al.Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'Microcephalin, a gene regulating brain size, continues to evolve adaptively in Humans'.Science. 2006; 313: 172Crossref PubMed Scopus (105) Google Scholar, 64Yu F. et al.Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens'.Science. 2007; 316: 370Crossref PubMed Scopus (41) Google Scholar]. Another study claimed that a MCPH1 haplotype, present in 70% of modern humans, originated from another hominid species [65Evans P.D. et al.Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 18178-18183Crossref PubMed Scopus (117) Google Scholar]. Such nucleotide-based analyses of MCPH are highly complex, however, and await careful validation by functional studies. Finally, the remains of a dwarfed microcephalic hominid found on the Flores Islands, Homo floresiensis, was speculated to be a case of either MOPD-II or MCPH [11Rauch A. et al.Mutations in the Pericentrin (PCNT) gene cause primordial dwarfism.Science. 2008; 319: 816-819Crossref PubMed Scopus (323) Google Scholar, 66Martin R.D. et al.Flores hominid: new species or microcephalic dwarf?.Anat. Rec. A: Discover. Mol. Cell. Evol. Biol. 2006; 288A: 1123-1145Crossref Scopus (86) Google Scholar] rather than a new hominid species. Further analysis has now supported the original theory that H. floresiensis was a separate hominid species that did exist, but became extinct [67Gordon A.D. et al.The Homo floresiensis cranium (LB1): size, scaling, and early Homo affinities.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 4650-4655Crossref PubMed Scopus (64) Google Scholar]. Despite the need for functional analyses of these changes, these reports provide exciting speculations about the development of humans as a species. As the Neanderthal genome nears completion, all the DNA changes separating modern humans from their closest hominid relative, who became extinct 30 000 years ago, will soon be known [68Dalton R. Neanderthal genome to be unveiled.Nature. 2009; 457: 645Crossref PubMed Scopus (2) Google Scholar]. Recent studies of the functions of MCPH proteins have produced some interesting results. Whereas previous studies indicating roles for ASPM in spindle organisation, CDK5RAP2 and CENPJ in transcriptional regulation and microtubule dynamics, or MCPH1 in DNA damage have been expanded upon, new roles and connections have been uncovered. Recent reports may begin to explain how these proteins influence neurogenesis, including a possible functional relationship between PCNT and MCPH1, and there is evidence to suggest that MCPH proteins have a role in the progression of other diseases (Box 2).Box 2Are MCPH proteins implicated in other diseases?As the MCPH proteins act in pathways affecting cell-cycle progression, proliferation and genome integrity, are there any indications of a contribution to pathogenesis in other diseases, such as cancer?Downregulation of ASPM expression resulting in delayed mitotic exit was observed upon expression of a Hepatitis C virus protein that reduces p38 MAPK activation [69Wu S.-C. et al.Hepatitis C virus NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway.J. Biol. Chem. 2008; 283: 29396-29404Crossref PubMed Scopus (47) Google Scholar]. It would be interesting to investigate whether ASPM expression status changes during subsequent tumourigenic transformation, as ASPM mRNA upregulation is correlated with disease progression and poor clinical outcome in both glioblastoma and primary hepatocellular carcinoma [29Horvath S. et al.Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 17402-17407Crossref PubMed Scopus (508) Google Scholar, 30Lin S.-Y. et al.ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma.Clin. Cancer Res. 2008; 14: 4814-4820Crossref PubMed Scopus (96) Google Scholar, 70Hagemann C. et al.Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas.Oncol. Rep. 2008; 20: 301-308PubMed Google Scholar, 71Marie S.K. et al.Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas.Int. J. Cancer. 2008; 122: 807-815Crossref PubMed Scopus (112) Google Scholar]. Additionally, ASPM was one of eight genes strongly upregulated in immortalised cells and cancer cells (although not in neuroblastoma) [72Jung H.M. et al.Expression profiles of SV40-immortalization-associated genes upregulated in various human cancers.J. Cell. Biochem. 2009; 106: 703-713Crossref PubMed Scopus (27) Google Scholar].Similarly, SIL mRNA is expressed in many tumours (except glioblastoma) and malignant cell lines from diverse tissues. Expression increases upon DNA synthesis induction; conversely, terminal differentiation or growth arrest leads to downregulation [51Izraeli S. et al.Expression of the SIL gene is correlated with growth induction and cellular proliferation.Cell Growth Differ. 1997; 8: 1171-1179PubMed Google Scholar, 73Erez A. et al.Sil overexpression in lung cancer characterizes tumors with increased mitotic activity.Oncogene. 2004; 23: 5371-5377Crossref PubMed Scopus (47) Google Scholar]. SIL relieves Gli1 inhibition through an interaction with suppressor of fused homolog (SUFU), and so promotes the transcription of target genes, including those encoding cyclin D1 and Patched; this interaction was enhanced by oncogenic K-Ras expression [74Kasai K. et al.SCL/TAL1 Interrupting Locus derepresses GLI1 from the negative control of Suppressor-of-Fused in pancreatic cancer cell.Cancer Res. 2008; 68: 7723-7729Crossref PubMed Scopus (60) Google Scholar]. Conversely, inducing SIL knockdown in a cancer cell line resulted in a G2/M growth arrest owing to delayed Cdk1 activation and increased apoptosis, suggesting that SIL is a potential therapeutic target [50Erez A. et al.The SIL gene is essential for mitotic entry and survival of cancer cells.Cancer Res. 2007; 67: 4022-4027Crossref PubMed Scopus (33) Google Scholar].As for CENPJ, its expression has been detected in breast cancer cell lines [1Cox J. et al.What primary microcephaly can tell us about brain growth.Trends Mol. Med. 2006; 12: 358-366Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar], although there are no recent studies building on this finding; and CDK5RAP2 downregulation has been recently linked to doxorubicin and paclitaxel resistance, commonly used in combination therapy for advanced breast cancer, suggesting that CDK5RAP2 could provide a pathway for tumour cells to evade destruction [75Zhang X. et al.CDK5RAP2 is required for spindle checkpoint function.Cell Cycle. 2009; 8: 1206-1216Crossref PubMed Scopus (37) Google Scholar].In contrast to the other MCPH genes, MCPH1 expression is downregulated in breast cancer cell lines, ovarian and prostate tumours, and is linked to increased genomic instability. Consequently, MCPH1 has been proposed as a potential tumour suppressor [1Cox J. et al.What primary microcephaly can tell us about brain growth.Trends Mol. Med. 2006; 12: 358-366Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar].What about patients with MCPH? Owing to practical difficulties, there has been little formal analysis of disease occurrence in such patients; however, anecdotal evidence suggests that the incidence of cancer is low, and possibly less than in the general population. Patients with MCPH do not appear to suffer from defective immune responses (centrosomes are involved in T-cell activation) or gut problems (a tissue that is dependent on maintaining stem cell divisions throughout life). However, although data are limited and based mainly on cell assays or mouse models, the current findings are interesting. As the MCPH proteins act in pathways affecting cell-cycle progression, proliferation and genome integrity, are there any indications of a contribution to pathogenesis in other diseases, such as cancer? Downregulation of ASPM expression resulting in delayed mitotic exit was observed upon expression of a Hepatitis C virus protein that reduces p38 MAPK activation [69Wu S.-C. et al.Hepatitis C virus NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway.J. Biol. Chem. 2008; 283: 29396-29404Crossref PubMed Scopus (47) Google Scholar]. It would be interesting to investigate whether ASPM expression status changes during subsequent tumourigenic transformation, as ASPM mRNA upregulation is correlated with disease progression and poor clinical outcome in both glioblastoma and primary hepatocellular carcinoma [29Horvath S. et al.Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 17402-17407Crossref PubMed Scopus (508) Google Scholar, 30Lin S.-Y. et al.ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma.Clin. Cancer Res. 2008; 14: 4814-4820Crossref PubMed Scopus (96) Google Scholar, 70Hagemann C. et al.Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas.Oncol. Rep. 2008; 20: 301-308PubMed Google Scholar, 71Marie S.K. et al.Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas.Int. J. Cancer. 2008; 122: 807-815Crossref PubMed Scopus (112) Google Scholar]. Additionally, ASPM was one of eight genes strongly upregulated in immortalised cells and cancer cells (although not in neuroblastoma) [72Jung H.M. et al.Expression profiles of SV40-immortalization-associated genes upregulated in various human cancers.J. Cell. Biochem. 2009; 106: 703-713Crossref PubMed Scopus (27) Google Scholar]. Similarly, SIL mRNA is expressed in many tumours (except glioblastoma) and malignant cell lines from diverse tissues. Expression increases upon DNA synthesis induction; conversely, terminal differentiation or growth arrest leads to downregulation [51Izraeli S. et al.Expression of the SIL gene is correlated with growth induction and cellular proliferation.Cell Growth Differ. 1997; 8: 1171-1179PubMed Google Scholar, 73Erez A. et al.Sil overexpression in lung cancer characterizes tumors with increased mitotic activity.Oncogene. 2004; 23: 5371-5377Crossref PubMed Scopus (47) Google Scholar]. SIL relieves Gli1 inhibition through an interaction with suppressor of fused homolog (SUFU), and so promotes the transcription of target genes, including those encoding cyclin D1 and Patched; this interaction was enhanced by oncogenic K-Ras expression [74Kasai K. et al.SCL/TAL1 Interrupting Locus derepresses GLI1 from the negative control of Suppressor-of-Fused in pancreatic cancer cell.Cancer Res. 2008; 68: 7723-7729Crossref PubMed Scopus (60) Google Scholar]. Conversely, inducing SIL knockdown in a cancer cell line resulted in a G2/M grow