Defective replication stress response linked to microcephaly

Abstract

Microcephaly primary hereditary (MCPH) is a rare, neurological disorder characterized by a small brain size, due to a lower number of neural progenitor cells, and mental retardation (Naveed in Genetics Research 100:e7, 2018). Approximately 40% of all MCPH patients harbor mutations in abnormal spindle-like microcephaly-associated (ASPM) gene, which is also known as MCPH5 (Létard in Human Mutation 39(3):319–32, 2018). The ASPM protein is involved in centriole duplication, orientation of the spindle, and regulation of mitosis (Jiang in Nature Cell Biology 19(5):480–492, 2017; Gai in EMBO Reports 17(10):1396–1409, 2016). Although these functions of ASPM seem to be independent of DNA replication, impaired DNA replication has been associated with microcephaly (Tingler in Biology of the Cell 114(6):143–159; Kalogeropoulou in Stem Cell Reports 17(6):1395–1410; Xu in Genome Instability & Disease 1:235–264). In a recent PNAS paper by Wu et al., the authors suggested that patients with mutations in ASPM harbor a reduced number of neuroprogenitor cells due to defects in the DNA stress response.