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

Abstract

The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in C. elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined sas-6(L69T) effect on centrosome duplication, ciliogenesis and dendrite morphogenesis. Our studies revealed that all the above processes 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, shorter phasmid dendrites 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 and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.

Highlighting rare disease research with a GENETICS and G3 series on genetic models of rare diseases

“…When overexpressed, E(z) A691G altered histone marks and caused a dramatic homeotic patterning defect relative to E(z) WT , suggesting that the variant can act in a dominant gain-of-function manner. Bergwell et al (2023) used CRISPR/Cas9 genome editing to develop a C. elegans model of autosomal recessive primary microcephaly through introduction of a mutation within the highly conserved core centriole gene, sas-6 . C. elegans carrying the pathogenic variant exhibited shortened phasmid cilia, abnormal cilia morphology, shorter dendrites, and chemotaxis defects.…”