glycosylation Archives - Sanford Burnham Prebys

Tag: glycosylation

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Parents gain answers about their child’s mysterious condition, thanks to SBP scientists

AuthorMonica May
Date

December 11, 2018

Hudson Freeze, PhD, Sanford Burnham Prebys

For the parents of a six-year-old Hispanic boy and a seven-year-old Qatari girl, answers remained elusive. Both children had alarming symptoms, including developmental delays, uncontrollable seizures and “floppy baby syndrome” (hypotonia). But despite doctors’ best efforts, the origin of the disease remained unknown. 

Now, these two children are linked by rare mutations in a gene called FUK—providing their families and doctors a better understanding of the cause of their medical conditions. Using biochemical techniques to analyze the boy’s cells, Sanford Burnham Prebys Medical Research Institute (SBP) scientists determined that a malfunctioning enzyme called fucokinase is to blame—caused by a mutation in the FUK gene. Because cells from the girl weren’t available, computer modeling was used—and indicated this same mutation likely caused the disease. The study published in the American Journal of Human Genetics.

Like a molecular spark plug, the fucokinase enzyme ignites one step in a cellular communication cascade—which culminates in the linkage of a sugar, fucose, to another carbohydrate. This final fucose-carbohydrate product is important for immune system regulation, tissue development, cell adhesion (“stickiness” to the environment) and more. 

Based on these findings, the scientists now know the condition is a congenital disorder of glycosylation (CDG), an umbrella term for disorders caused by abnormal linking of sugars to cellular building blocks, including proteins, fats (lipids) and carbohydrates. Although more than 130 types of CDGs exist, the boy and girl are the only known living individuals who have this mutation. 

“Our hope is that by reporting this information, we will help doctors grant more answers to patients and their loved ones,” says Hudson Freeze, PhD, senior author of the paper and director and professor of the Human Genetics Program at SBP. “Based on our findings, genetic databases around the world will now note this mutation causes disease—a potentially life-changing shortcut in the quest for answers.” 

The researchers analyzed skin and immune cells that were collected from the boy. They observed reductions in the amount of the fucokinase enzyme—as much as 80 percent in skin cells and more than half in immune cells, compared to a control protein. Consistent with these findings, downstream products typically created by fucokinase weren’t incorporated into the final fucose-carbohydrate product—indicating the enzyme was not working.

Because cells from the girl were not available, the scientists used computer modeling to predict the impact of her FUK gene mutation. This approach indicated the mutation occurs at an important site on the enzyme that would likely cause disease.

“We know that dampening down the activity of the FUK gene is linked to metastatic cancer—a deadly event that occurs when tumors gain the ability to travel throughout the body,” says Freeze. “In addition to providing long-awaited answers to these families, these findings could help us understand how certain cancers spread throughout the body, including liver, colorectal and skin cancers (melanoma).” 

Both children were identified through the National Institutes of Health’s Undiagnosed Diseases Network, which is designed to accelerate discovery and innovation in the way patients with previously undiagnosed diseases are diagnosed and treated. 

Additional study authors include: Jill Rosenfeld, Lisa Emrick, MD, Lindsay Burrage, MD, PhD, Brendan Lee, MD, PhD, William Craigen, MD, PhD, Baylor College of Medicine; Mahim Jain, MD, PhD, Johns Hopkins School of Medicine; David Bearden, MD, University of Rochester School of Medicine; and Brett Graham, MD, PhD, Baylor College of Medicine and Indiana University School of Medicine. The study’s DOI is https://doi.org/10.1016/j.ajhg.2018.10.021

Research reported in this story was supported by National Institutes of Health (NIH) grants R01DK099551, U01HG007709, and K08DK106453; Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (U54 HD083092), Diana & Gabriel Wisdom and the Rocket Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

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Uncovering the cause of a 12-year-old girl’s rare neurological disorder

AuthorSusan Gammon
Date

September 25, 2017

DNA research with a sample. Hand with a test tube on a DNA background shutterstock_653790793.jpg

The parents of a child with seizures, weak muscles, limited communication abilities and autism-like behavior problems recently got a long-awaited answer as to the cause of her disorder. Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identified the genetic variants causing this now 12-year-old girl’s neurological issues.

“One of the many tests performed by the specialists treating her suggested that her symptoms might stem from problems with the addition of sugars to proteins,” says Hudson Freeze, PhD “That’s why they came to us. There are lots of ways that the protein modification process—called glycosylation—can go wrong. We specialize in figuring out precisely which gene is responsible for an individual patient’s disease, using sequencing and measurements of cellular activities.”

Publishing in the American Journal of Medical Genetics, Freeze’s team showed that the patient carries variant sequences in both copies of a gene called SLC35A1, which encodes a protein that transports a specific sugar into the part of the cell where it’s used to modify proteins.

“She inherited two different mutations in the same gene from each of her parents,” says Bobby Ng, research assistant in the Freeze lab and lead author of the study. “Those mutations prevent the transporter protein from working, so that a crucial sugar—sialic acid—is missing from the ends of the sugar chains on many proteins located on the surface of cells.”

“Sialic acid is critically important for the function of a protein called NCAM that’s needed for the brain to develop properly,” Ng adds. “We think that’s why this patient’s problems are mostly neurological.”

This is only the third reported case of disease caused by mutations in the SLC35A1 gene. Ng, Freeze, and their collaborators had to devise entirely new assays to confirm that the mutations impaired transport of sialic acid and its attachment to proteins.

These three cases make up one class of a broader group of disorders known as CDGs, for congenital disorders of glycosylation. All CDGs are rare, but Freeze nonetheless believes strongly in the value of understanding them.

“CDGs may not be common, but many of them are extremely severe, affecting development and the function of multiple organs,” he says. “For the families whose children have a CDG, they’re the most important diseases in the world. And the only way we’ll ever find specific treatments that address their root causes is by investigating the pathology of each one.”

Institute News

Study triples the number of known cases of a rare disease

Authorjmoore
Date

March 10, 2016

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A recent paper from the laboratory of Hudson Freeze, PhD, characterizes 39 previously unreported cases of a specific type of congenital disorder of glycosylation (CDG). CDGs, the focus of research in Freeze’s lab in SBP’s Sanford Children’s Health Research Center, are rare inherited disorders. CDG symptoms, which can include developmental delay, movement problems, and impaired function of multiple organs, differ depending on the underlying mutation. Continue reading “Study triples the number of known cases of a rare disease”

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You’re invited to Rare Disease Day at Sanford-Burnham in La Jolla

Authorsgammon
Date

February 9, 2015

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Did you know that in the United States there are more people with a rare disease than people with cancer and AIDS combined?

Rare Disease Day is an internationally recognized day to raise awareness about rare diseases and their impact on patients’ lives. There are more than 6,000 types of rare diseases, and most of them are genetic disorders that affect children. The term “rare disease” is a designation of disorders that affect fewer than 200,000 individuals. For most rare-disease patients, the rarity of their disorder makes the process of an accurate diagnosis a significant challenge—requiring extensive genetic and biochemical tests. Equally, if not more, challenging is the search for effective treatments to improve the health and lives of those that suffer. Continue reading “You’re invited to Rare Disease Day at Sanford-Burnham in La Jolla”