Review
What primary microcephaly can tell us about brain growth

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Autosomal recessive primary microcephaly (MCPH) is a neuro-developmental disorder that causes a great reduction in brain growth in utero. MCPH is hypothesized to be a primary disorder of neurogenic mitosis, leading to reduced neuron number. Hence, MCPH proteins are likely to be important components of cellular pathways regulating human brain size. At least six genes can cause this disorder and four of these have recently been identified: autosomal recessive primary microcephaly 1 (MCPH1), abnormal spindle-like, microcephaly associated (ASPM), cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) and centromere protein J (CENPJ). Whereas aberration of ASPM is the most common cause of MCPH, MCPH1 patients can be more readily diagnosed by the finding of increased numbers of ‘prophase-like cells’ on routine cytogenetic investigation. Three MCPH proteins are centrosomal components but have apparently diverse roles that affect mitosis. There is accumulating evidence that evolutionary changes to the MCPH genes have contributed to the large brain size seen in primates, particularly humans. The aim of this article is to review what has been learnt about the rare condition primary microcephaly and the information this provides about normal brain growth.

Section snippets

Emerging phenotypes and genotypes of primary microcephaly

Microcephaly is characterized by reduced skull circumference, measured from the forehead to the occipital prominence at the back of the head, which closely correlates with reduced brain volume. The greater the degree of microcephaly, the greater the risk and severity of mental retardation. Although there are numerous causes of microcephaly, this review focuses only on autosomal recessive primary microcephaly (MCPH). Brain size of affected individuals is similar to that of early hominids,

Clinical features of MCPH

At birth, the human brain is approximately three times larger than that of our closest primate relatives [1]. Brain growth occurs both in the pre- and post-natal period (in the first three years of human life, the brain becomes four times bigger than that at birth). The human skull is designed to accommodate this change through growth of skull bones and delayed closure of the sutures between the skull bones. Head circumference (HC) is a useful indirect measurement of brain size. Although

MCPH genes and their function

MCPH is expected to exhibit genetic heterogeneity due to its broad clinical phenotype. Six autosomal recessive loci (MCPH1–MCPH6) have been identified 11, 12. Each locus was mapped using the same methodology: a single large, multi-affected consanguineous family was used and autozygosity mapping was performed using microsatellite markers or single nucleotide polymorphisms (SNPs) spaced throughout the human genome [13]. Heterogeneity and mutation detection studies suggest that MCPH5 (where the

The MCPH1/Microcephalin gene

The MCPH1/Microcephalin gene is a 14-exon gene that encodes an 835 amino acid protein on chromosome 8p23. It was identified by positional cloning within an ancestral haplotype shared by two consanguineous Pakistani families [16]. Affected individuals in both families were homozygous for an early truncating mutation in the gene (S25X), and the previously uncharacterised MCPH1 protein was named microcephalin. The gene was shown to be expressed in foetal mouse brain during the period of

The functions of MCPH1/microcephalin

The 835 amino acid MCPH1/microcephalin protein is predicted to contain three breast cancer 1 (BRCA1) C-terminal (BRCT) domains [21]. One BRCT domain is present at the N-terminus and two at the C-terminus of MCPH1/microcephalin (Figure 2) [16]. The closest homologues of MCPH1/microcephalin are BRCA1 and topoisomerase-II-binding protein, owing to their shared BRCT domains. Because these and other BRCT-domain-containing proteins contribute to DNA repair or cell-cycle control, it has been proposed

The MCPH5/ASPM gene

Homozygous mutation of the MCPH5 gene, also known as abnormal spindle-like microcephaly-associated gene (ASPM), is the most common cause of the MCPH phenotype 7, 14. The orthologue of the Drosophila gene abnormal spindle (asp) is a 28-exon gene spanning ∼63 kb of genomic DNA and contains ten 10 434-base-pair open reading frames [10]. The pathogenic nature of mutations in the MCPH5/ASPM gene is a truncation that does not result in nonsense-mediated decay, as it would be expected, but in the

The function of ASPM as a spindle pole protein

Using bioinformatic analysis and species comparison, the 3477 amino acid ASPM protein has been predicted to contain one N-terminal microtubule-binding domain, two calponin homology domains (common in actin-binding proteins), 81 Ile–Gln repeat motifs, which are predicted to undergo a conformational change when bound to calmodulin, and a C-terminal region of unknown function 10, 32, 34, 35. Thus, structural projections suggest that ASPM directly interacts with the intracellular cytoskeleton and

The MCPH3/CDK5RAP2 gene encodes a centrosomal protein

Mutations in MCPH3 and MCPH6 genes are a rare cause of MCPH. Both encode centrosomal components, further emphasizing the importance of the centrosome in the central nervous system 7, 14, 45, 46. The MCPH3 locus harbours the 34-exon gene cyclin-dependent kinase 5 regulatory associated protein 2 (CDK5RAP2) [17]. Two truncating mutations have been reported, c.243T > A (S81X) and IVS26–15A > G (E385fsX4), which creates a novel intronic splice acceptor sequence 15 bases before the normal start of exon

The MCPH6/CENPJ gene also encodes a centrosomal protein

The MCPH6 gene is also known as centromere-associated protein J (CENPJ, or centrosomal protein 4.1-associated protein CPAP) 12, 17, 50. Two Northern Pakistani pedigrees have been reported with the same truncating mutation in exon 2, c.17_18delC (T6fsX3). In the original family used to map the MCPH6/CENPJ locus, a homozygous missense mutation, c.3704A > T (E1235V), in exon 16 was identified. This mutation, which occurs in a highly conserved position in the t-complex 10 (TCP10) binding domain of

Neuro-developmental aetiology of MCPH

MCPH is hypothesized to be a primary disorder of neurogenic mitosis [53]. Evidence for this prediction includes: (i) all four known MCPH genes are expressed in the neuro-epithelium of the developing brain 15, 16, 17; (ii) the majority of MCPH proteins are centrosomal components; (iii) all four have (predicted) roles in mitosis; and (iv) the defining phenotypic feature of MCPH is likely to be a uniform reduction in production of central nervous system neurons. However, it remains to be

Concluding remarks

MCPH is a neuro-developmental disorder that leads to a substantial reduction in the number of neurons produced during foetal development. Four of the causative genes have been identified and current evidence of their function suggests that MCPH is a primary disorder of neurogenic mitosis. However, the exact and non-redundant roles of the MCPH products await further experimentation (Box 2). Also, the identification of the remaining MCPH genes is still lacking. With this additional information,

Additional notes

Since the original submission of this review, three novel ASPM nonsense mutations have been reported in Pakistani MCPH families [69]. In one additional family, a homozygous non synonymous change c.9539A > C (Q3180P) was found in the 79th IQ domain of ASPM. Functional proof that this is a pathogenic mutation is awaited.

Acknowledgements

We thank A. Nicholas and three anonymous reviewers for their positive contribution to this review. We also thank M. Bateman and L. Monkman (Department of Cytogenetics, Addenbrooke's Hospital, Cambridge, UK).

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