Alan McStravick for redOrbit.com – Your Universe Online
A recent study, conducted by researchers at the Washington University School of Medicine in St. Louis and their partners at the Joslin Diabetes Center in Boston and the Novartis Institutes for Bio Medical Research, has managed to identify a specific genetic mechanism connected to mutations in the WFS1 gene that affects insulin-secreting beta cells.
It is believed that this discovery will be paramount in increasing the understanding of the rare genetic disorder Wolfram Syndrome (WS) and may also be an important development in the treatment of milder forms of diabetes and related disorders. The full study has been published online in the journal Nature Cell Biology.
Wolfram Syndrome is a rare genetic condition that is caused by mutations in a single gene. This minute mutation, however, has far reaching effects on the body leading to conditions such as diabetes, hearing and vision loss and nerve cell damage that can cause motor difficulties and, ultimately, early death.
WS was first observed in 1938 as a combination of familial juvenile-onset diabetes and optic atrophy. It was understood even then that for most of the patients with this progressive disorder, premature death and widespread atrophic changes throughout the brain were the most probable outcomes. This insulin-requiring type of diabetes typically develops at around age 6.
Examination showed that pancreatic islets were atrophic and the insulin-producing beta cells were selectively absent. WS is believed to account for 1 out of every 150 patients suffering from juvenile or adolescent onset insulin-requiring diabetes mellitus.
The mechanism by which WS works is still unknown, although in 1994 researchers discovered a link between the WFS1 gene and genetic markers on the 4p chromosome.
The reported frequency of those who carry the recessive genetic trait in the U.S. population is approximately 1%. While those that carry the recessive trait do not necessarily show the full range of WS symptoms, they are at a higher risk of developing various forms of mental illness.
Full-fledged WS only occurs in the offspring of two parents who both carry the recessive form of the gene WFS1, and multiple incidences within a genetically predisposed family are not uncommon. There doesn´t appear to be any increase or decrease in frequency based on the sex of the offspring.
As we currently understand WS, it is the result of either nuclear or mitochondrial genetic dysfunction. In addition to diabetes mellitus, other typical symptoms include diabetes insipidus, impaired vision and hearing loss. Additional WS complications can include urinary tract and seizure disorders.
Treatments for WS depend on the patient´s specific symptoms, but common treatments include therapies of thiamin and vitamin B6. With successful therapy, WS patients very often can decrease their dependence on insulin, and related complications like anemia may be eradicated entirely.
In this most recent study, led by Fumihiko Urano, associate professor of medicine at Washington University´s Division of Endocrinology, Metabolism and Lipid Research, the understanding of WS and its accompanying symptoms was greatly increased.
“We found something we didn´t expect,” said Urano. “The study showed that the WFS1 gene is crucial to producing a key molecule involved in controlling the metabolic activities of individual cells.”
The molecule referenced is called cyclic adenosine monophosphate (cyclic AMP), a naturally occurring molecule that rises in response to high blood sugar, which in turn causes insulin-secreting beta cells in the pancreas to produce and secrete insulin.
“I would compare cyclic AMP to money,” explained Urano. “You can´t just take something you make to the store and use it to buy food. First, you have to convert it to money. Then, you use that money to buy food. In the body, external signals stimulate a cell to make cyclic AMP, and then the cyclic AMP, like money, can ℠buy´ insulin or whatever else may be needed.”
Urano went on to say that the primary reason that patients suffering from WS experience so many problems is because mutations in the WFS1 gene interfere with cyclic AMP production in beta cells in the pancreas.
“In patients with WS, there is no available WFS1 protein, and that protein is key in cyclic AMP production. Then, because levels of cyclic AMP are low in insulin-secreting beta cells, those cells produce and secrete less insulin. And in nerve cells, less cyclic AMP can lead to nerve cell dysfunction and death.”
By linking the production of cyclic AMP to mutations in the WFS1 gene, Urano´s team has given future researchers a new, more specific target for WS research.
“I don´t know whether we can find a way to control cyclic AMP production in specific tissues. But if that´s possible, it could help a great deal,” said Urano.
While WS is a rare condition, affecting only about 1 in 500,000 people, Urano says the findings also may be important in the treatment of more common disorders.
“It´s likely this mechanism is related to diseases such as type 2 diabetes. If a complete absence of the WFS1 protein causes WS, perhaps a partial impairment leads to something milder, like diabetes.”
Funding for this research was provided by the JDRF, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Center for Research Resources of the National Institutes of Health (NIH).