Richard L. Eckert, PhD, University of Maryland, Baltimore, MD
Haibing Jiang, PhD, Eckert Laboratory , University of Maryland, Baltimore, MD
Dr. Richard Eckert Dr. Haibing Jiang
It has been known for nearly a decade that the type I transglutaminase gene is mutated in at least 50% of all cases of autosomal recessive congenital ichthyosis (ARCI). However, understanding how these mutations lead to disease pathology is not well understood. As part of an effort to better understand the cause of this disease, Dr. Richard Eckert and colleag ues at the University of Maryland School of Medicine in Baltimore recently studied the subcellular processing of normal and mutant transglutaminase in human skin cells. These studies, which were spearheaded by Dr. Haibing Jiang of the Eckert laboratory, have led to potentially important new insights regarding the pathology of this disease.


Autosomal recessive congenital ichthyosis (ARCI) is a debilitating genetic inherited skin disorder that affects 1 in every 200,000 to 300,000 people.  It includes Lamellar Ichthyosis (i.e. the plate-like scales) and CIE (i.e. congenital ichthyosiform erythroderma).  Mutations of several genes are observed in this group of diseases and one of the genes is type I transglutaminase (TGM1).  TGM1 protein is required for skin maturation, and TGM1 mutation results in deficient epidermal cornification leading to an abnormal epidermal surface, including the production of plate-like “fish” scales. TGM1 mutations are found in a significant percentage of ARCI patients.
To study the role of TGM1 in this disease, these investigators delivered TGM1 mutants to normal human skin cells and found that these mutant proteins accumulate at an abnormal location inside the cell. Dr. Jiang remarks that “the finding that mutant forms of TGM1 are abnormally distributed inside skin cells was a surprise.” This accumulation is in the endoplasmic reticulum (or ER), which is a processing and quality control center for new proteins being synthesized in the cell. When mutant proteins are not properly folded, they accumulate within the ER for removal from the cell. Sometimes, mutant proteins accumulate within the ER and cannot be successfully removed, and this leads to cell death.
Appropriate folding is required for TGM1 function. “We believe that mutant TGM1 accumulates in the ER because it is not properly folded and that this accumulation of TGM1 in the ER leads to reduced TGM1 function and alters skin cell maturation and may also cause cell death,” comments Dr. Eckert. The authors predict that using chemicals to restore normal folding of mutant TGM1 may alleviate some of the disease processes and symptoms. To test this idea, Dr. Jiang showed that treatment with chemicals that enhance protein folding reduces accumulation of mutant TGM1 in the ER.

Although additional research is necessary, we believe that identification of this novel mechanism is a significant step forward in our understanding of ichthyosis and that it may lead to therapies that enhance appropriate folding of mutant TGM1 leading to restoration of TGM1 function. This may help alleviate the ichthyosis-related symptoms. This work was presented in July at the prestigious “Transglutaminases in Human Disease Processes” Gordon Research Conference at Davidson College in Davidson, North Carolina; a scientific manuscript describing this work will soon appear 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, Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis. J. Biol. Chem., in press)


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