While researchers have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome, it remained to be determined how WFS1 mutations cause diabetes and neurodegeneration.
In a study published online February 15 in the Journal of Clinical Investigation, Fumihiko Urano, MD, PhD, associate professor in gene function and expression and molecular medicine at UMMS, and M. Alan Permutt, MD, professor of internal medicine and cell biology at WUSTL School of Medicine, and their colleagues demonstrated that the normal WFS1 gene has a function in reducing a special type of cell stress called endoplasmic reticulum stress (ER stress), and that mutations in the gene cause the accumulation of abnormal proteins in cells. Such chronic ER stress in pancreatic beta cells and neurons leads to insulin-dependent diabetes mellitus and neurodengeneration common in Wolfram Syndrome. Other studies have suggested that ER stress-mediated cell death plays a role in the pathogenesis of diabetes and neurodegeneration in animal models of such diseases. Seeking to understand how WFS1 mitigates cellular stress, the team developed a mouse model in which they could delete the WFS1 gene and study the effect. They also used lymphocytes from sibling pairs in which one sibling has Wolfram syndrome and one does not. These findings are the first to show that ER stress causes beta cell death and neurodegeneration in human disease.
“Currently, no treatment can slow the progression of Wolfram Syndrome; thus, our discovery is an important first step towards designing a novel therapeutic modality for the syndrome,” said Dr. Urano. “Studying rare diseases, such as Wolfram Syndrome, in which there is a single genetic defect, is tremendously helpful because it allows researchers to focus on the function of a specific gene or protein that is often involved in other, more common diseases. Indeed, recent approaches using candidate-genes and studies of genome-wide associations revealed that genetic variations in the WFS1 gene are associated with type 2 diabetes.”
“This study by Dr. Urano and team provides novel insights into the cell components which may govern beta cell protection or lead to loss of beta cells,” said Patricia Kilian, Ph.D., Director of Regeneration at the Juvenile Diabetes Research Foundation, which helped fund the study. “If ways can be found to increase expression of WFS-1, it may open up new approaches to reverse or prevent loss of beta cells as a therapeutic strategy for diabetes.”
“Dr. Urano is doing cutting-edge work on the role of the Wolfram protein on mechanisms of ER stress and cell damage,” said Dr. Permutt.
Named for the physician who first described it in the 1930s, Wolfram Syndrome is caused by the lack of the WFS1 gene and can result in a constellation of other disorders, including diabetes insipidus and optic nerve atrophy, which leads to blindness. Although it is difficult to estimate the number of patients worldwide—in part because the disorder is often misdiagnosed—there are believed to be only a few hundred known cases in the US. The rarity of the disease not only makes it difficult for physicians to become familiar with and recognize the symptoms, it also hinders research into possible treatment.
Late last year, Urano and colleagues established a research collaborative through which scientists and clinicians worldwide can work towards developing new treatments for this rare disorder. The collaborative, which includes experts from the United States, Europe, Japan and the Middle East, grew out of a meeting initiated and organized under the auspices of the Association du Syndrome de Wolfram in France, presided over by Nolwen Jaffre, mother of a child with the syndrome, with the help of the Association Francaise contre les Myopathies (the French Muscular Dystrophy Association). Designed to leverage individual investigations into the disorder and maximize treatment options for people with the syndrome, the collaborative is led by Urano and Permutt and will create an international patient registry, write clinical guidelines and research guidelines, publish a meeting report, and establish periodic multi-specialty clinics for Wolfram syndrome patients. The patient registry will help researchers better define the clinical aspects of Wolfram Syndrome, identify patients for future clinical trials and to collect DNA for genetic studies and blood cells for research into disease mechanisms.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School, one of the fastest growing academic health science centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $240 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit www.umassmed.edu.
About Washington University School of Medicine in St. Louis
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare. For more information, visit http://medicine.wustl.edu.