Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings

Abstract

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.

Figure 1

The MCPH proteins, probable functional domains, and sites of mutations. The MCPH loci and protein names are given above a cartoon of the protein. The known or well-predicted domains are shown. Reported mutations are shown at their positions within the gene: nonsense mutations as filled arrows, splicing mutations that lead to premature termination codons as blackened arrows with marked tail, and a missense mutation as an unfilled arrow. Parallel lines indicate the translocation breakpoint in the ASPM gene described by Pichon et al. (2004). Each MCPH protein is marked with the known or hypothesized functional domains. Br is a BRCT Breast Cancer Suppressor Protein (BRCA1) carboxy-terminal domain, pfam00533. SMC is a chromosome segregation ATPase domain, COG1196, but all are only possible predictions. CH is calponin homology domain, pfam00307. IQ repeats is an isoleucine-glutamine calmodulin-binding domain, pfam00612. Tcp is a T-complex protein 10 C-terminus domain, pfam07202.

Figure 2

Encephalization in primates. The relative encephalization of various primate species was mapped on a phylogeny of primates (Goodman 1999). Data on brain weight and body weight was taken from Marino (1998) for apes, Old World monkeys, and New World monkeys and from Stephan et al. (1981), as given by Clark et al. (2001), for prosimians. The encephalization quotient (i.e., the ratio of observed brain weight to expected brain weight) is given in parentheses. The range is given when the data from several species are collapsed in the tree. The expected brain weight was calculated from a linear regression on log transformed brain and body weights for the Marino data, excluding humans (brainweight=10exp(0.6765×bodyweight+2.3406)). Species showing at least a 1.4-fold–heavier brain than expected for their body weights are marked by rectangles.