C. elegansmodels of Marfan and Marfan-like Syndromes reveal trafficking defects of the type II TGFβ receptor as a potential novel disease mechanism
Authors: Lin Jing , Vora Mehul , Kane Nanci S. , Gleason Ryan J. , Padgett Richard W. 
Published: December 2018

AbstractThe transforming growth factor-β (TGFβ) family plays an important role in many developmental processes and when mutated often contributes to various diseases. Marfan syndrome is a genetic disease with an occurrence of approximately 1 in 5,000. The disease is caused by mutations in fibrillin, which lead to an increase in TGFβ ligand activity, resulting in abnormalities of connective tissues which can be life-threatening. Mutations in other components of TGFβ signaling (receptors, Smads, Schnurri) lead to similar diseases with attenuated phenotypes relative to Marfan syndrome. In particular, mutations in TGFβ receptors, most of which are clustered at the C-terminal end, result in Marfan-like (MFS-like) syndromes. Even though it was assumed that many of these receptor mutations would reduce or eliminate signaling, in many cases signaling is active. From our trafficking work inC. elegans, we noticed that many of these receptor mutations that lead to Marfan-like syndromes overlap with mutations that cause mis-trafficking of the receptor, suggesting a link between Marfan-like syndromes and TGFβ receptor trafficking. To test this hypothesis, we introduced some of these key MFS and MFS-like mutations into theC. elegansTGFβ receptor and asked if receptor trafficking is altered. We find that some of the mutated receptors localize to the apical surface rather than basolateral surface of the polarized intestinal cells. Further, we find that these mutations result in longer animals, a phenotype due to over-stimulation of the pathway and, importantly, indicating that function of the receptor is not abrogated in these mutants. Our nematode models of Marfan syndrome suggest that MFS and MFS-like mutations in the type II receptor lead to mis-trafficking of the receptor and possibly provides an explanation for the disease, a phenomenon which might also occur in some cancers that possess the same mutations within the type II receptor (e.g. colon cancer).Author SummaryThe transforming growth factor-β (TGFβ) family plays an important role in many basic biological processes and when mutated often contributes to various diseases. Marfan syndrome (MFS) is a genetic disease with an occurrence of approximately 1 in 5,000. The disease is caused by mutations in fibrillin, which lead to an increase in TGFβ ligand activity, resulting in abnormalities of connective tissues which can be life-threatening. However, some patients with normal fibrillin genes also show symptoms and pathologies associated with Marfan syndrome, known collectively as Marfan-like Syndromes (MFS-like). When these patients were assessed for mutations in other components of the TGFβ pathway, several mutations clustered in a small region of the receptors, primarily in the type II TGFβ receptor were found.We find that mimicking these mutations in the nematode type II TGFβ receptor causes the mutant receptor to move to regions of the cell where it is not normally found. Importantly, these mutations do not abrogate the function of the receptor, suggesting that mis-localization of the receptor might be previously unknown cause of disease etiology. We hypothesize that receptor mutations present at the LTA lead to disruptions in interactions with trafficking regulators leading to symptoms of MFS/MFS-like syndromes – a novel disease mechanism of MFS/MFS-like syndromes that might also extend to other cancers bearing similar mutations.