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School of Medicine Researcher Has Identitfied Genetic Mutation In Debilitating Skin Disorder ARCI

Wednesday, November 17, 2010

 Dr. Eckert and colleagues hope the discovery could lead to new treatments for the devastating effects of ARCI.

A recent study from the Department of Biochemistry and Molecular Biology has identified a genetic mutation that seems to be critical to a debilitating inherited skin disorder called autosomal recessive congenital ichthyosis (ARCI). The researchers hope the discovery could lead to new treatments for the devastating condition, according to the paper published recently in the Journal of Biological Chemistry. The senior author  is Richard L. Eckert, Ph.D., the John F.B. Weaver Distinguished Professor and Chair, Department of Biochemistry and Molecular Biology.

Ichthyosis, as the disease is commonly known, affects one in every 200,000 to 300,000 people. There are many types of ichthyosis, including Lamellar Ichthyosis, in which the skin is covered with large, hard, dark-colored scales. Another type is Congenital Ichthyosiform Erythroderma (CIE), characterized by fine, light-colored scales and intense redness of the skin. The disease usually presents in newborn babies or in the first year of life, and affects 16,000 babies every year. The disease is disfiguring and devastating to patients, and there is no cure.

Dr. Eckert and his team, including lead author Haibing Jiang, Ph.D., research associate, Department of Biochemistry and Molecular Biology, examined the functioning of a particular gene known as type I transglutaminase (TG1). There are mutations of several genes found commonly in the group of conditions known as ichthyosis, and TG1 is one of those mutated genes.

“TG1 protein is required for skin maturation, and mutation of the gene results in deficiencies in epidermal cornification, the process by which cells form an epidermal barrier,” explained Dr. Eckert. “Mutation of TG1 is found in a significant percentage of ichthyosis patients. It leads to the abnormal skin surface we see in these patients, in which they are covered with plate-like fish scales. In fact, the disease takes its name from these fish scales, from the prefix ‘ichthy’ as the Greek root for the word fish.”

To better understand the role of TG1 in ichthyosis, the scientists delivered mutated TG1 to normal human skin cells. They found that the mutant proteins accumulate at an abnormal location inside the cell, in the endoplasmic reticulum (ER). The ER is a processing and quality control center for new proteins being synthesized in the cell. When mutant proteins are not properly synthesized or folded — a process in which they become active, three-dimensional structures — they remain inactive and accumulate within the ER for removal from the cell. When inactive proteins accumulate here and cannot be successfully removed, they result in cell death.

“We know that proper folding is required for TG1 function, and when we see mutant TG1 accumulated in the ER, we assume it is not properly folded,” said Dr. Jiang. “This accumulation leads to reduced TG1 function in these patients. It alters skin cell maturation and may also cause cell death. The good news is that this discovery may mean new hope for ichthyosis patients.”

The scientists believe that using chemicals to restore normal folding of mutant TG1 could alleviate some of the disease processes and symptoms. In fact, their research found that treatment with chemicals to enhance protein folding reduces accumulation of mutant TG1 in the ER.

“Though additional research is necessary, we believe that indentifying this novel mechanism is a significant step forward in our understanding of ichthyosis,” said Dr. Eckert. “We hope this may lead to new therapies to restore the function of this mutated gene and alleviate these terrible symptoms.”

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