gene mutation contributing factor research

[Guest guest]

Hi all

This was on the American Diabetes Association newsletter this week

but it has implications for MS and other immune related diseases as

well.

Hope it doesn't seem to off the track to share with you all.

regards

Sadie

12-JUL-2004

Genetic Mutation Found that is Major Contributor to Type 1 Diabetes

AUGUSTA, Ga., July 11 (AScribe Newswire) -- A natural mutation of a

gene that helps regulate the reactivity of the immune system is a

major contributor to type 1 diabetes, Medical College of Georgia

researchers have found.

The newly discovered gene, SUMO-4, controls the activity of NFkB, a

molecule that in turn controls the activity of cytokines, proteins

that regulate the intensity and duration of the immune response,

according to research that will be published in the August print

issue of Nature Genetics and online July 11.

By examining the transmission of genes from parents to children in

nearly 1,000 diabetic families from around the world, the

researchers found that a certain natural mutation of that SUMO-4

gene increases the risk of type 1 diabetes.

....snip...

" The mutation we have found is going to increase the responsive

capacity of the immune system to environmental triggers or

stimulators; it makes it more reactive, " said Dr. Cong-Yi Wang,

molecular geneticist and co-senior author.

Dr. Wang and his research team found that when that mutation

encounters an environmental trigger, such as a bacterial or viral

infection, it throws off the usual well-balanced activity of the

immune system, initiating an autoimmune response that eventually

attacks the patient's own tissue.

They already are exploring the gene's potential role in other

autoimmune diseases as well such as lupus, thyroid disease,

arthritis and multiple sclerosis.

SUMO-4 is the fourth gene identified that contributes to type 1

diabetes, taking a place just behind HLA, another regulator of

immunity, in terms of relative risk. " Many genes are involved in

type 1 diabetes, but this is one of the most important ones, " said

Dr. She.

He leads a research team that has followed diabetic families

primarily in Florida and Georgia for the past 10 years to find

precisely how genes, the immune system and the environment work

together to cause type 1 diabetes, a childhood disease that requires

a lifetime of taking insulin. Like its lifestyle-related

counterpart, type 2 diabetes, the incidence of type 1 has increased

dramatically: a near 300 percent increase in the last 20 years.

This is one of the few times scientists have successfully used a

systematic approach to finding a gene involved in a complex disease

such as diabetes. The MCG researchers narrowed their search for

diabetes-related genes by looking at those most often transmitted to

children with diabetes, Dr. She said. That approach compares with

traditional forward genetics - a cumbersome process they liken to

looking for a needle in a haystack - which narrows the search by

predicting which of some 40,000 genes might be involved in a disease

based on what scientists already know about the disease and the

genes.

" You guess the function, you guess the disease possibilities, then

you guess which genes might be involved in the pathogenesis, " Dr.

She said. " As a community, we have guessed right a few times,

including identification of HLA. But this is the first time we have

used a systematic approach to find the gene and it's the first gene

in which we know how it contributes to the disease. "

For example, HLA is a regulator of immunity that has been known for

30 years, but researchers still don't know exactly how it causes

diabetes. The MCG team has found that SUMO-4 encodes a protein that

modifies the activity of NFkB. It was already known that NFkB

regulates the production of certain cytokines and that cytokines

have a role in type 1 diabetes as well as other autoimmune diseases.

What wasn't known was the cause of the excessive cytokine production

seen in those diseases. Now they know that SUMO-4 regulates the

activity of NFkB, which in turn regulates whether cytokine

production is on autopilot, shut down or revved up.

The SUMO-4 mutation they found overrides the systems that put

cytokine production on autopilot or shut it down. Instead, it

enables cytokine production not only to increase but directs the

increased immune response at the insulin-producing beta cells of the

pancreas.

Dr. She credits many for the findings but especially Dr. Wang for

his diligence in working through this more systematic - but still

extremely tedious - approach to identifying not only the gene but

how it causes disease.

" This is the reason scientists stay in science, " Dr. She

said. " These are the days you look for, days when you can make a

difference, not just for science, but for humanity, for patients,

for people who have diabetes and, perhaps even more, for people who

are going to develop diabetes. " He noted that none of the work would

be possible without the contributions of study families. " We are

trying to improve their lives, but without them, we cannot do

anything. "

The studies were funded by National Institute of Child Health and

Development and the Juvenile Diabetes Research Foundation.

Collaborators included researchers at the University of Florida;

Endocrinologia, Instituto Clinica Medica II, University of Rome; the

University of Southern California School of Medicine, Los Angeles;

Cedars-Sinai Medical Center and the University of California, Los

Angeles; Hanyang University Hospital in Korea; Facultad de Medicina,

Universidad Complutense in Madrid; HLA Laboratory, Beijing Red Cross

Blood Center, China; and Unite de Recherches de 1'INSERM U580,

Centre de l'Association Claude Bernard, France.

CONTACT: Toni Baker, MCG Media Relations, 706-721-4421, beeper 706-

723-1401, tbaker@...

---

The Medical College of Georgia is the state's health sciences

university and includes the Schools of Allied Health Sciences,

Dentistry, Graduate Studies, Medicine and Nursing, the MCG Medical

Center and the Children's Medical Center. Please visit our Web site

at http://www.mcg.edu .

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