New Research Links Altered Sugar Modifications to Marfan Syndrome Symptoms
Marfan syndrome, a genetic disorder causing a diverse range of symptoms from skeletal abnormalities to cardiovascular issues like weakened aortic walls, has long presented a molecular puzzle. While the mutations causing the syndrome are known, how they translate into these varied health problems remained unclear. Recent research from the University of Georgia, led by Nicholas Kegley and Professor Robert Haltiwanger, has uncovered a crucial link: alterations in a process called O-glucosylation – the addition of glucose sugars to the protein fibrillin-1.
The study reveals that marfan syndrome-associated mutations in fibrillin-1 lead to unexpected changes in this sugar modification. Previous work from the Haltiwanger lab established that fibrillin-1 is heavily modified by enzymes POGLUT2 and POGLUT3, which attach single glucose molecules to serine amino acids within the protein. deletion of these enzymes proved fatal in newborn animal models and resulted in abnormal fibrillin-1 in the lungs, highlighting their importance.
Initially, researchers believed POGLUT2 and POGLUT3 required a very specific amino acid sequence to function. However, the new research demonstrates that a less stringent sequence containing serine is sufficient for glucose attachment, significantly expanding the potential number of proteins these enzymes can modify.
To investigate the impact of Marfan mutations,the team introduced mutations found in patients into fibrillin-1 and analyzed the sugar modifications using mass spectrometry. They discovered that, contrary to expectations, some mutations caused an increase in glycosylation – the addition of multiple glucose sugars where typically only one would be present. Other mutations resulted in reduced glycosylation.
“Typically, the wild-type version of the protein has the O-glucose monosaccharide, which is one sugar,” explained Kegley. “But some of the Marfan variants had extra sugars stacked up on top.”
Haltiwanger suggests these changes in glycosylation could impact how fibrillin-1 interacts with the extracellular matrix (ECM), potentially increasing its breakdown by enzymes called proteases, or altering its binding to other ECM proteins. These disruptions could contribute to the symptoms experienced by Marfan syndrome patients.
This finding of elongated sugar modifications was particularly surprising, as it had not been previously observed in decades of fibrillin-1 research. Haltiwanger estimates that the broadened understanding of POGLUT2 and POGLUT3’s target sequences suggests nearly twice as many human proteins could be subject to their modification than previously thought.
Future research will focus on understanding how these altered sugar modifications affect fibrillin-1’s incorporation into microfibrils, its susceptibility to degradation, and its interactions with other proteins within the ECM. This work, according to Kegley, not only deepens our understanding of Marfan syndrome but also underscores the growing importance of glycobiology – the study of sugars – in health and disease, potentially paving the way for new treatments for Marfan syndrome and related fibrillinopathies.
