The Genetic Cause of a Rare, Neurodevelopmental Disorder
Summary
- An international research group led by scientists at the University of Miami Miller School of Medicine identified the mutated gene WSB2 as a deterrant to neural development and function.
- When healthy, WSB2 helps mark proteins for destruction. The mutation cripples this important activity, allowing aberrant proteins to accumulate.
- This discovery creates a broader understanding of how WSB2 variations can contribute to neurodevelopmental disorder.
An international research group, led by scientists at the University of Miami Miller School of Medicine, has identified a novel gene associated with a neurodevelopmental condition. The mutated gene, WSB2, is part of a critical cellular system that recycles unneeded proteins. Without this process, bad proteins accumulate, hampering neural development and function. The study was published in the European Journal of Human Genetics.
“We’ve worked on this gene and the associated phenotype for several years,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School’s Department of Pediatrics and Jackson Health System. “We started with one patient carrying this recessive, loss-of-function WSB2 mutation and were unsure what it meant. Thanks to collaborations from around the world, we can now say this is the disease-causing mechanism, which opens many possibilities, including helping diagnose other patients and even finding treatments.”
Losing a Critical Cellular System
While cells are constantly churning out new proteins, these molecules are never meant to last forever. At the far end of this process, a cellular system called the proteosome destroys redundant proteins and recycles their raw materials.
In this intricate but orderly process, cells tag unneeded proteins with a molecule called ubiquitin.
When healthy, WSB2 helps attach ubiquitin, marking proteins for destruction. However, the mutation cripples this important activity, allowing aberrant proteins to accumulate.
The study focused on five patients, from four families, who shared a variety of traits, including neurodevelopmental delays, brain structure issues, smalls heads, low body weight at birth, autism and other symptoms.
The multinational research team, which included co-authors from the U.S., Germany, Israel, Qatar and Singapore, used computational tools to model WSB2 to determine how these mutations would impact protein function and neurodevelopment. The group also recapitulated the loss of function in mouse models, which closely matched the traits found in the human patients.
“We suspected this protein is important to neurological function, but now we have clear proof based on the patients we found, the types of mutations and the models,” said Dr. Agrawal. “All these things are telling us this is a truly important protein that, when mutated, will cause these neurological issues.”
Gene Mutation and Neurodevelopment
This discovery creates a broader understanding of how WSB2 variations can contribute to this neurodevelopmental disorder and possibly others. The group will continue to investigate how this protein functions to better understand its impact. Eventually, they hope this work will lead to treatments, such as gene replacement, that could help patients overcome their conditions.
“This is the first step in a long journey,” said Dr. Agrawal. “Now that we’ve identified this link to WSB2, it will give doctors a new tool to help diagnose patients and perhaps get them better care. It can also support better family planning. More research needs to be done, but the ultimate goal is better therapies.”
Tags: Department of Pediatrics, Dr. Pankaj Agrawal, genetics, genomics, pediatrics