A Coffin-Siris syndrome-associated mutation modeled in Caenorhabditis elegans affects multiple developmental processes.

Coffin-Siris syndrome (CSS) is a rare human genetic disorder that is characterized by developmental delay, fifth digit abnormalities, and craniofacial defects. Heterozygous mutations in 2 SoxC proteins, SOX4 and SOX11, are associated with this disorder. Caenorhabditis elegans has a single SoxC protein, SEM-2, which is essential for development. In this study, we use C. elegans as a model system to explore the molecular effects of one CSS-associated SOX11 mutation, Y116C, on SoxC protein function in vivo. The equivalent amino acid of SOX11 Y116 is SEM-2 Y160, a residue in the C-terminal tail of the highly conserved DNA-binding domain. Homozygous, but not heterozygous, sem-2[Y160C] animals exhibit a high rate of embryonic and larval lethality, egg-laying defects, reduced brood size, bivulval phenotype and a low penetrance of hermaphrodite tail abnormalities. Additionally, sem-2[Y160C] animals have reduced expression of hlh-8/Twist, whose human counterparts, when mutated, are known to be associated with craniofacial disorders. All the phenotypes observed in sem-2[Y160C] animals resemble SEM-2 loss-of-function phenotypes, suggesting that SOX11[Y116C] is a loss-of-function, recessive mutation that likely causes defects due to haploinsufficiency. Our work suggests that using C. elegans as a model system to analyze the molecular effects of point mutations associated with craniofacial defects has the potential for unraveling the underlying mechanisms.