Molecular genetics of human primary microcephaly: an overview

Abstract

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1 and CDK6. It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder.

Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum

“…Interestingly, CDK5RAP2 gene has an important role in neocortical expansion during brain development and its expression is particularly high within the brain, more specifically within the thalamus and corpus callosum and then strongly downregulated with brain maturation. 9 More specifically, CDK5RAP2, which encodes for an 1833 amino-acid protein, has a major role in the microtubuleorganizing function of the centrosome through interaction with the γ-tubulin ring complex (γTuRC) that mediates microtubule nucleation through a binding site localized between amino acids 58 and 90. 10 Any alteration of this binding site has been shown to cause defects on γTuRC-targeting to the centrosome, and therefore to deregulate neurogenic cell divisions.…”

BRCT-domain protein BRIT1 influences class switch recombination

“…BRIT1 also mapped to one of the 12 loci implicated in primary microcephaly (hence the name microcephalin or MCPH1), an autosomal recessive disease characterized by severely decreased cerebral cortex and varying degrees of mental retardation (17,18). This ∼110-kDa ubiquitously expressed protein with one N-terminal and two tandem C-terminal BRCT domains has been demonstrated to be a crucial proximal regulator of DDR (19).…”

Replication of early and recent Zika virus isolates throughout mouse brain development

“…Mutations in genes critical for these processes all may interfere with the proper number of neurons and layers, resulting in a thinner neocortex, consistent with autosomal recessive microcephaly (reviewed in ref. 9).…”