How sugars shape Marfan syndrome
Most people associate sugar glucose with sweet treats, but it also plays a critical role in protein function. In fact, new research from the Journal of Biological Chemistry suggests that variations in protein glucosylation may contribute to diseases like Marfan syndrome.
Marfan syndrome is an autosomal dominant genetic disorder caused by mutations in the gene that encodes fibrillin-1. Fbrillin-1 is an essential component of the extracellular matrix, or ECM. When mutated, fibrillin-1 disrupts tissue integrity and can contribute to diseases like Marfan syndrome or other disorders known as fibrillinopathies.

The mutations present in Marfan patients causes a wide range of symptoms that include skeletal deformities, increased joint flexibility and cardiovascular impacts. For example, affected individuals may have weakened aortic walls that increase their risk of rupture, but how these mutations contribute to symptoms on a molecular level is unclear.
This new study was conducted by Nicholas Kegley, a former graduate student and current postdoctoral researcher, and Robert Haltiwanger, a professor at the University of Georgia. They found that Marfan syndrome–associated mutations in fibrillin-1 lead to unexpected in changes in O-glucosylation, the addition of glucose to a specific amino acid, serine, in the protein.
“A lot of people think these sugar modifications are just decorations,” Haltiwanger said. “But our lab is showing there is something more going on, they have relevant biological functions. We are helping to determine what that is.”
This research builds on earlier findings from the Haltiwanger lab showing that fibrillin-1 is heavily modified by two enzymes: POGLUT2 and POGLUT3. These enzymes attach single glucose molecules to a serine in short repeating motifs in fibrillin-1. They found that genetic deletion of both enzymes resulted in neonatal lethality and abnormal fibrillin-1 in the lungs. These findings highlighted the enzymes’ importance and spurred further investigation into their substrate specificity.
Initially, they thought that POGLUT2 and POGLUT3 required a strict amino acid motif to add glucose. However, they found that a less strict motif containing a serine is sufficient — significantly broadening the enzymes’ potential target sequences.
To explore how Marfan mutations alter fibrillin-1 glycosylation, the team introduced known patient mutations into the protein and used mass spectrometry to analyze the sugar modifications.
“Typically, the wild-type version of the protein has the O-glucose monosaccharide, which is one sugar.” Kegley said. “But some of the Marfan variants had extra sugars stacked up on top. This means you could have two or three sugars where you typically should have just one.”
Haltiwanger added that while some mutations elongated the modifications, others reduced the glycosylation. Overall, this means these changes may influence how fibrillin-1 integrates into the ECM, increase its degradation by proteases, or binding to proteins in the ECM. One or all of these could be contributing to the symptoms patients experience.
“This finding (of elongation) was completely surprising,” Kegley said. “People have been studying fibrillin-1 for decades and hadn’t found this.”
Based on these findings, Haltiwanger estimates that nearly twice as many human proteins could be targets for POGLUT2 and POGLUT3 modification than previously thought.
Future directions include investigating how these sugar modifications affect fibrillin-1 incorporation into microfibrils, its susceptibility to degradation, or binding to proteins that normally bind to fibrillin-1 in the ECM. According to Kegley, this work not only improves our understanding of Marfan syndrome but also expands the growing appreciation for glycobiology as a key player in health and disease.
“We know fibrillin is implicated in disorders that affect large numbers of people. This work opens new avenues for experimentation,” says Kegley. “There’s still a lot to learn about how significant these findings could be for the Marfan syndrome community and others affected by fibrillinopathies — but it may eventually help guide the development of new treatments.”
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