CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly

Autosomal recessive primary microcephaly(MCPH) is characterized by a substantial reduction in brain sizebut with normal architecture. It is often linked to mutations in genes coding for centrosomalproteins; however, their role in brain sizeregulation is not completely understood. By combining homozygosity mapping and whole- exome sequencingin an MCPH family from Pakistan, we identified a novel mutation (XM_011518861.1; c.4114C > T) in CDK5RAP2, the gene associated with primary microcephaly-3 (MCPH3), leading to a premature stop codon(p.Arg1372*). CDK5RAP2is a component of the pericentriolar materialimportant for the microtubule-organizing function of the centrosome. Patient-derived primary fibroblasts had strongly decreased CDK5RAP2amounts, showed centrosomaland nuclear abnormalities and exhibited changes in cell size and migration. We further identified an interaction of CDK5RAP2with the Hippo pathway components MST1kinase and the transcriptional regulator TAZ. This finding potentially provides a mechanism through which the Hippo pathway with its roles in the regulation of centrosomenumber is linked to the centrosome. In the patient fibroblasts, we observed higher levels of TAZ and YAP. However, common target genes of the Hippo pathway were downregulated as compared to the control with the exception of BIRC5 (Survivin), which was significantly upregulated. We propose that the centrosomaldeficiencies and the altered cellular properties in the patient fibroblasts can also result from the observed changes in the Hippo pathway components which could thus be relevant for MCPH and play a role in brain sizeregulation and development.