A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication and ciliogenesis in Caenorhabditis elegans

A missense mutation within the human SASS6 gene has been linked with the incidence of primary microcephaly in a Pakistani family. However, the mechanism by which this mutation causes disease is still unclear. SASS6 protein function is conserved between humans and C. elegans . Therefore, in the present study, we used C. elegans to model this primary microcephaly-associated mutation to determine which molecular pathways are affected by this mutation in C. elegans . The human primary microcephaly-associated mutation corresponds to SAS-6(L69T) in C. elegans . Our studies revealed that both centrosome duplication and ciliogenesis are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, defective phasmid dendrite morphology and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Based on our findings, we propose that the ciliogenesis defects induced by this mutation are likely a more important contributing factor to the development of primary microcephaly in humans carrying this mutation than centrosome duplication defects. Thus, our studies shed light on a novel mechanism by which the sas-6(L69T) mutation could lead to the incidence of primary microcephaly in humans.