Scientists at Sanford Burnham Prebys Medical Discovery Institute and an international team of collaborators announced on April 13 that they have discovered a new rare genetic disease using whole exome sequencing. The findings were published on April 3 in Human Genetics and Genomics Advances, identifying a mutated gene linked to the disorder.
The discovery is significant because it expands the understanding of congenital disorders of glycosylation (CDG), which are caused by mutations affecting glycosylation—a process where cells build long sugar chains that attach to proteins. Glycosylation is essential for protein stability and function, and when impaired, can result in serious malfunctions across various organ systems.
Researchers began their study by sequencing the genomes of two siblings with an unknown neurodevelopmental disorder. They identified a mutation shared by these siblings but not present in three other unaffected siblings. This particular genetic error had not been previously reported in public databases used for diagnosing rare diseases.
The scientists focused on a mutation in the RPN1 gene, which encodes ribophorin I—a protein involved in glycosylation. Biochemical tests confirmed patterns consistent with known CDGs. "The glycosylation results from these tests reflected patterns we know well from other CDGs," said Hudson Freeze, PhD, William W. Ruch Distinguished Endowed Chair and director of the Sanford Children's Health Research Center at Sanford Burnham Prebys.
Freeze added: "After confirming that this was a new CDG, the next step was to better understand why it was occurring." The team found that the mutation truncated ribophorin I, causing instability within one subtype of the oligosaccharyltransferase (OST) complex called OST-A. This led to reduced attachment of sugars to many proteins targeted by OST-A.
By defining this new disease—now termed RPN1-CDG—the number of genes associated with OST complex diseases has increased to eight. A deeper understanding may help provide more accurate diagnoses for patients suffering from rare diseases.
