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

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Coffin-Siris syndrome (CSS) is a rare genetic disorder linked to SOX4 and SOX11 gene mutations.
• SOX11 mutations cause developmental delay and craniofacial defects.
• C. elegans SEM-2 is a homologous SoxC protein crucial for development.

Purpose of the Study:

• To investigate the in vivo molecular effects of a CSS-associated SOX11 mutation (Y116C) using C. elegans.
• To determine if the SOX11 Y116C mutation impacts SEM-2 protein function.
• To explore the potential of C. elegans as a model for studying CSS mechanisms.

Main Methods:

• Generated a C. elegans mutant with the equivalent of the human SOX11 Y116C mutation in the SEM-2 gene (sem-2[Y160C]).
• Phenotypically characterized homozygous and heterozygous sem-2[Y160C] animals.
• Assessed the expression of the hlh-8/Twist gene in sem-2[Y160C] mutants.

Main Results:

• Homozygous sem-2[Y160C] mutants exhibited significant embryonic lethality, developmental defects, and reduced brood size.
• The sem-2[Y160C] mutation resulted in reduced expression of hlh-8/Twist.
• Phenotypes observed were consistent with SEM-2 loss-of-function, indicating the mutation is recessive.

Conclusions:

• The CSS-associated SOX11 Y116C mutation functions as a recessive loss-of-function mutation in C. elegans.
• This mutation likely causes CSS-related defects through haploinsufficiency.
• C. elegans serves as a valuable model for dissecting the molecular basis of craniofacial defects in CSS.