Molecular and cellular basis of autosomal recessive primary microcephaly

Abstract

Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.

Figure 1

Centrosome structure. Centrosomes are small organelles composed of two perpendicular centrioles (orange cylinders), a mother and a daughter, linked together by interconnecting fibres (dark green). The centrioles are surrounded by an amorphous pericentriolar matrix (dotted orange background) involved in the nucleation and anchoring of cytoplasmic microtubules. Contrary to the daughter centriole, the mother centriole possesses distal (purple) and subdistal (blue) appendages necessary for cilia assembly and microtubule anchoring, respectively.

Figure 2

Microcephaly protein interaction network. The majority of microcephaly proteins (red) are associated with centrosomes. CENPJ, STIL, and CEP135 are components of centrioles (green box), while MICROCEPHALIN, CDK5RAP2, and CEP152 are part of the PCM (orange background). WDR62, ASPM, and CDK6 temporarily localize to the PCM. In addition, CASC5 and PHC1 are known to interact with proteins at the centrosome. For ZNF335, its precise connection to the centrosome is not understood. Microcephaly proteins are physically linked to one another either directly or indirectly (solid black lines) to form a protein network.

Figure 3

Cellular processes involved in microcephaly. A model depicting how malfunction of microcephaly proteins perturbs neurogenesis. A loss of microcephaly proteins can disturb various cellular processes, including chromatin remodelling, kinetochore integrity, centrosome biogenesis, or centrosome maturation, which impair cell cycle checkpoints and mitosis. These perturbations disrupt the equilibrium between cell proliferation and cell death, symmetric and asymmetric division, and/or normal and abnormal differentiation, reducing the total number of neuroprogenitor cells and differentiated neurons in the developing brain, leading to microcephaly.