Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths.

Although nearly 10% of Americans suffer from a rare disease, clinical progress in individual rare diseases is severely compromised by lack of attention and research resources compared to common diseases. It is thus imperative to investigate these diseases at their most basic level to build a foundation and provide the opportunity for understanding their mechanisms and phenotypes, as well as potential treatments. One strategy for effectively and efficiently studying rare diseases is using genetically tractable organisms to model the disease and learn about the essential cellular processes affected. Beyond investigating dysfunctional cellular processes, modeling rare diseases in simple organisms presents the opportunity to screen for pharmacological or genetic factors capable of ameliorating disease phenotypes. Among the small model organisms that excel in rare disease modeling is the nematode Caenorhabditis elegans. With a staggering breadth of research tools, C. elegans provides an ideal system in which to study human disease. Molecular and cellular processes can be easily elucidated, assayed and altered in ways that can be directly translated to humans. When paired with other model organisms and collaborative efforts with clinicians, the power of these C. elegans studies cannot be overstated. This Review highlights studies that have used C. elegans in diverse ways to understand rare diseases and aid in the development of treatments. With continuing and advancing technologies, the capabilities of this small round worm will continue to yield meaningful and clinically relevant information for human health.

Saul-Wilson Syndrome Missense Allele Does Not Show Obvious Golgi Defects in a C. elegans Model.

Saul-Wilson Syndrome is an ultra-rare skeletal syndrome caused by a mutation in the COG4 gene resulting in a glycine-to-arginine substitution at amino acid position 516. The COG4 gene encodes one of 8 subunits of the conserved oligomeric Golgi complex. Using CRISPR-Cas9, our lab generated a C. elegans model for Saul-Wilson Syndrome by recreating the same glycine-to-arginine substitution in the worm ortholog cogc-4. Upon observation, the cogc-4(av107) worms did not display any obvious differences compared to wild-type worms. We used a variety of assays including stressing the worms using heat and Paraquat, as well as RNAi against the 7 other COG complex subunit genes in an attempt to uncover a phenotype. Our data suggest that this mutation in cogc-4(av107) worms does not lead to a detectable phenotype. Further studies should aim at more directly assessing Golgi function in this disease model.