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 Caenorhabditis elegans. Given that S...

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Published in:Genetics (Austin) 2023-08, Vol.224 (4)
Main Authors: Bergwell, Mary, Smith, Amy, Smith, Ellie, Dierlam, Carter, Duran, Ramon, Haastrup, Erin, Napier-Jameson, Rebekah, Seidel, Rory, Potter, William, Norris, Adam, Iyer, Jyoti
Format: Article
Language:English
Subjects:
Animals
Caenorhabditis elegans
Caenorhabditis elegans - genetics
Caenorhabditis elegans Proteins - genetics
Cell Cycle Proteins - genetics
Centrioles - genetics
Centrosome
Chemotaxis
Cilia
Defects
Dendrites
Genetic Models of Rare Diseases
Humans
Microcephaly
Microcephaly - genetics
Microencephaly
Missense mutation
Morphogenesis
Morphogenesis - genetics
Mutation
Nematodes
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Summary: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 Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the 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. Bergwell, Smith et al. reveal that a primary microcephaly-associated sas-6(L69T) mutation affects centrosome duplication, dendrite morphogenesis, and ciliogenesis in C. elegans. The authors show that worms carrying the sas-6(L69T) mutation exhibit mild defects in centrosome duplication and stronger defects in ciliogenesis and dendrite extension; phasmid cilia and dendrite length, cilia morphology, and chemotaxis are all defective in sas-6(L69T) mutant worms. Their results shed light on the possible mechanisms by which this mutation could contribute to primary microcephaly in humans.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1093/genetics/iyad105