Scientists at the Sanford Burnham Prebys Medical Discovery Institute and a team of international collaborators have discovered a new rare genetic disease using a genetic sequencing technique called whole-exome sequencing.
The researchers published their findings on April 3, 2026. Advances in human genetics and genomics Identify defective mutated genes. By investigating the biochemical effects of the mutation, the researchers also showed that this typo in the genetic code interferes with normal cell function, as expected for an unknown congenital disorder of glycosylation (CDG).
CDG is a collective term for more than 190 diseases caused by mutations that impair glycosylation, the complex process by which cells build long sugar chains and attach them to proteins to produce glycoproteins. These sugar chains, called glycans, have been found to modify most secreted proteins. They play many important roles, including ensuring protein stability and proper folding. Allows biological functions to be carried out.
When glycosylation is impaired, sugar molecules on many of the body’s proteins are missing or incomplete, causing severe and often fatal dysfunction in various organ systems throughout the body. Because glycosylation has many functions, CDG can cause a variety of symptoms and outcomes, and accurate diagnosis or initial discovery of these diseases requires biochemical testing and genome sequencing.
In the new study, scientists began by sequencing the genomes of two siblings suffering from a neurodevelopmental disorder of unknown cause. They found a mutation shared by the two affected siblings, but not by the other three siblings, who showed no signs of the disease. This genetic error had not been reported to the large public database that geneticists use to share information around the world to help each other diagnose and research rare diseases.
These results led scientists to focus on mutations within the body. RPN1 gene. This gene contains the blueprint for building a protein called ribophorin I. Because this protein plays a role in glycosylation, the research team performed a biochemical test used to diagnose CDG patients by assessing whether the protein is properly modified with sugar molecules.
“The glycosylation results in these tests reflected patterns well known from other CDGs,” said Dr. Hudson Freese, William W. Ruch Distinguished Endowed Chair and director of the Sanford Child Health Research Center at Sanford Burnham Prebys.
“Once we confirmed that this was a new CDG, the next step was to better understand why it happened.”
Ribophorin I, the protein affected by the newly identified mutation, is an essential component of the complex biological machinery responsible for glycosylation. Multiple proteins, including ribophorin I, combine to form two types of cellular factories known as oligosaccharyltransferase (OST) complexes. These binding proteins work together to modify newly assembled proteins with appropriate sugar molecules.
The researchers found that this mutation cuts out part of ribophorin I, destabilizing the protein in the OST complex. Cleavage of ribophorin I also caused a unique defect in one of the two subtypes of the OST complex, called OST-A. This structural defect reduced the binding of sugars to many proteins that OST-A is supposed to glycosylate.
The OST complex plays a role in all developmental processes, which is why CDG exhibits a variety of neurodevelopmental and other developmental problems. ”
Dr. Hudson Freese, William W. Ruch Special Endowed Chair and Director of the Sanford Child Health Research Center at Sanford Burnham Prebys
By defining and studying this new disease, now named RPN1-CDG, scientists expanded the number of genes associated with the OST complex disease to eight. A better understanding of new diseases and all CDGs will help provide definitive diagnoses to more patients suffering from rare diseases.
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Reference magazines:
N, B.G. others. (2026). Homozygous nonsense mutants of the oligosaccharyltransferase complex gene RPN1 cause congenital glycosylation defects. Advances in human genetics and genomics. DOI: 10.1016/j.xhgg.2026.100604. https://www.cell.com/hgg-advances/pdf/S2666-2477(26)00044-8.pdf
