Understanding Autosomal Recessive Ichthyosis (2012)

FIRST Supports Gordon Research Conference

For the second year FIRST provided financial support for the Gordon Research Conference.  This year’s conference was held over the summer at Davidson College in Davidson, North Carolina.
Richard Eckert, PhD,  Professor and Chair, John F.B. Weaver Distinguished Professor, Biochemistry and Molecular Biology at University of Maryland, and Kapil Metha, PhD, Professor of Cancer Medicine (Biochemistry),  University of Texas MD Anderson Cancer Center, submitted a summary about the skin disease-relevant work presented at the conference.
Richard Eckert, PhD,  Professor and Chair, John F.B. Weaver Distinguished Professor, Biochemistry and Molecular Biology at University of Maryland
Kapil Metha, PhD, Professor of Cancer Medicine (Biochemistry),  University of Texas MD Anderson Cancer Center

 

 

 

Understanding Autosomal Recessive Congenital Ichthyosis

Richard L. Eckert, PhD
Professor and Chair
John F.B. Weaver Distinguished Professor
Biochemistry and Molecular Biology

Kapil Mehta, PhD
Professor of Cancer Medicine (Biochemistry),
University of Texas M.D. Anderson Cancer Center

Autosomal recessive congenital ichthyosis (ARCI) is an inherited genetic disease that affects 1 of every 250,000 people.  It includes lamellar ichthyosis (i.e. the plate-like scales) and CIE (i.e. congenital ichthyosiform erythroderma).  The type I transglutaminase (TG1) gene is mutated in many of these disease patients.  The TG1 protein is required for skin maturation and mutation of this protein results in deficient epidermal cornification leading to an abnormal epidermal surface including the production of plate-like “fish” scales.  TG1 mutations are found in a significant percentage of ARCI patients; however, understanding how these mutations lead to disease pathology is not well understood.

In an effort to understand the role of TG1 mutations in disease, Dr. Richard Eckert and colleagues at the University of Maryland-School of Medicine in Baltimore are studying the intracellular events that control processing of normal and mutant TG1 in normal human skin cells.  These studies have led to potentially important new insights regarding the pathology of this disease.

These investigators found accumulation of mutant TG1 protein at abnormal locations inside cells.  This finding that the mutant TG1 proteins accumulate in the endoplasmic reticulum (ER) was “remarkable and not previously observed”, comments Dr. Eckert.  The ER is a protein processing and quality control center that checks new proteins as they are synthesized in the cell.  Unlike normal TG1, mutant TG1 proteins accumulate in the ER and are not successfully transported to the plasma membrane.  This is in contrast to normal TG1 which passes through the endoplasmic reticulum and is deposited on the inner surface of the plasma membrane where it aids cell maturation.

Mutant TG1 appears to not be appropriately folded and therefore accumulates in the ER and never arrives at the plasma membrane.  Since there is less TG1 at the plasma membrane there is reduced TG1 activity.  Dr. Eckert is presently testing the idea that treatment with chemicals that restore normal folding of mutant TG1 may alleviate some of the disease symptoms.  Indeed, Eckert laboratory studies show that treatment with chemicals that enhance protein folding reduces accumulation of mutant TG1 in the ER and increases TG1 activity.

Dr. Eckert states that “identification of this novel mechanism is an important step that will enhance our understanding and may lead to new therapies for this disease”.  An initiate discussion of this work was presented in July 2010 at the prestigious “Transglutaminases in Human Disease Processes” Gordon Research Conference at Davidson College in Davidson North Carolina and continued at the July 2012 meeting.  A manuscript describing some of these findings was published in the Journal of Biological Chemistry (Jiang-H, Jans-R, Xu-W, Rorke-EA, Lin-CY, Chen-YW, Fang-S, Zhong-Y and Eckert-RL JBC 285:31634, 2010 and a second manuscript is in preparation.

 


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