Trends in Molecular Medicine
ReviewWhat primary microcephaly can tell us about 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).
References (70)
- et al.
Evolution of primary microcephaly genes and the enlargement of primate brains
Curr. Opin. Genet. Dev.
(2005) Human microcephaly
Curr. Opin. Neurobiol.
(2004)Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter
Am. J. Hum. Genet.
(1998)Protein-truncating mutations in ASPM cause variable reduction in brain size
Am. J. Hum. Genet.
(2003)Identification of microcephalin, a protein implicated in determining the size of the human brain
Am. J. Hum. Genet.
(2002)Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition
Am. J. Hum. Genet.
(2002)Mutations in microcephalin cause aberrant regulation of chromosome condensation
Am. J. Hum. Genet.
(2004)The BRCA1 C-terminal domain: structure and function
Mutat. Res.
(2000)Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1
J. Biol. Chem.
(2004)- et al.
Multiple tumor suppressor pathways negatively regulate telomerase
Cell
(2003)
Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome
Cell
DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency
Mol. Cell
The homeotic target gene centrosomin encodes an essential centrosomal component
Cell
Centrosome duplication and nematodes: recent insights from an old relationship
Dev. Cell
Depletion of CPAP by RNAi disrupts centrosome integrity and induces multipolar spindles
Biochem. Biophys. Res. Commun.
Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings
Am. J. Hum. Genet.
Genesis of the primate neostriatum: [3H]thymidine autoradiographic analysis of the time of neuron origin in the rhesus monkey
Neuroscience
Asymmetric cell division: fly neuroblast meets worm zygote
Curr. Opin. Cell Biol.
Accelerated evolution of nervous system genes in the origin of Homo sapiens
Cell
Malformations of the central nervous system
The predictive value of microcephaly during the first year of life for mental retardation at seven years
Dev. Med. Child Neurol.
Microcephaly
Microcephaly
Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation
J. Med. Genet.
The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype
Hum. Mutat.
Radiologic classification of malformations of cortical development
Curr. Opin. Neurol.
ASPM is a major determinant of cerebral cortical size
Nat. Genet.
A novel locus for autosomal recessive primary microcephaly (MCPH6) maps to 13q12.2
J. Med. Genet.
A new method for autozygosity mapping using single nucleotide polymorphisms (SNPs) and EXCLUDEAR
J. Med. Genet.
Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations
Clin. Genet.
A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size
Nat. Genet.
SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly
Hum. Genet.
Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II
Cell Cycle
BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1–Chk1 pathway, implicating checkpoint dysfunction in microcephaly
Proc. Natl. Acad. Sci. U. S. A.
A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome
Nat. Genet.
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