Matthew Herman
The term ichthyosis refers to a variety of different scaling disorders, ranging from the relatively common ichthyosis vulgaris (IV) to recessive X-linked ichthyosis (RXLI) and epidermolytic ichthyosis (formerly called EHK). Our lab has been studying yet another kind of ichthyosis: autosomal recessive congenital ichthyosis (ARCI).

ARCI is rare, with an estimated occurrence of 1:200,000-1:300,000 in the US. The term ARCI refers to lamellar ichthyosis (LI), non-bullous congenital ichthyosiform erythroderma (NBCIE), and the extremely rare harlequin ichthyosis (HI). Mutations are changes in the base sequence of genes (the genetic code represented by the letters A, T, C, and G) that cause a change in a part of the body's inner machinery, and ARCI is associated with mutations of genes that reside on autosomal chromosomes. Humans have 22 autosomal chromosomes. Non-autosomal chromosomes, the chromosomes X and Y, are associated with sex determination. Humans possess two copies of all autosomal chromosomes (and therefore two copies of every gene on those chromosomes). ARCI is recessive, which means that, in order for someone to develop ARCI, an individual must have one mutation in each copy of a single gene that could potentially cause ARCI. ARCI is called congenital, since it appears at birth or shortly thereafter. Newborns who will develop ARCI are often born in a tight translucent sheath called a collodion membrane, and these newborns are often referred to as collodion babies. Five genes that cause ARCI have been identified. A recent study by our lab found that the most often mutated gene in North Americans with ARCI is called the transglutaminase-1 gene (TGM1 gene). TGM1 encodes the enzyme transglutaminase-1 that helps to build the cornified envelope, which is a barrier in the skin that protects against heat loss, water loss, and infection. The epidermis, the outer layer of the skin, consists of four different layers. From innermost to outermost, they are the basal, spinous (spiny), granular, and cornified (horny) layers. Skin cells mature as they move from the basal layer outward until they die and form the cornified layer. The transglutaminase-1 enzyme builds the cornified envelope in the upper granular layer as skin cells are changing from granular layer cells to cornified layer cells called keratinocytes. Therefore, healthy keratincoytes possess a cornified envelope.

When there are mutations in the TGM1 gene, the transglutaminase-1 enzyme stops working properly and the cornified envelope does not develop. Enzymes are complex molecules that perform different jobs in our cells. Most enzymes, including transglutaminase-1, are proteins, which are made up of many small parts called amino acids. Sometimes mutations cause a change in one amino acid to another which prevents the enzyme from working properly. Many different mutations in the TGM1 gene are associated with ARCI and have been reported in the scientific literature. Most (71%) of the mutations in the TGM1 gene, which cause ARCI, result in changes of a single amino acid to a different amino acid. Our lab recently reported on 23 new mutations found in patients who were registered with the National Registry for Ichthyosis and Related Skin Disorders. Our novel mutations brought the total number of distinct mutations to 115.

The job of the transglutaminase-1 enzyme is to create a bond, called a cross-link. This cross-link holds together structural proteins, including involucrin, loricrin and filaggrin, all of which are building blocks of the cornified envelope. After these proteins are cross-linked, they are deposited on the inside of the skin cells' membrane, like insulation deposited on the inside of a house. Calcium initiates this cross-linking activity. Most (54%) of the TGM1 mutations reside in the functional part of the enzyme that is known as the catalytic core. The other parts of transglutaminas-1 are more structural in nature. Some skin cells, which have these mutations in their TGM1 gene, have had their transglutaminase-1 cross linking activity measured experimentally. The keratinocytes from ARCI patients with TGM1 mutations all showed transglutaminase-1 enzyme cross-linking activity below 10% that of transglutaminase-1 enzymes taken from the cells of healthy patients.

There is a lot of clinical variation in patients with mutations in TGM1. For instance, patients who have lamellar ichthyosis (LI) have dark plate-like scales, and patients who have NBCIE have whitish scales and erythroderma (redness). Most people with TGM1 mutations fall into one of these two categories of ARCI. Others have variants on these two categories, one of which is called bathing suit ichthyosis (BSI), where scales develop only on the trunk and scalp. Some people are born with another variant of ARCI known as self-healing collodion baby (SHCB). These babies have a collodion membrane, which is quickly shed, and develop healthy or minimally ichthyotic skin. Mutations in TGM1 have not been reported in patients with harlequin ichthyosis (HI), the third class of ARCI, which is associated with large dark scales that restrict movement and breathing and results from too little ABCA12 transporter. All of these types of ichthyosis can be inherited and first appear at birth.

In addition to reporting and classifying 23 new mutations and reviewing previous literature, we created a database, where we deposited our new mutations and those previously reported. We used the Leiden Open (source) Variation Database (LOVD) to create our own TGM1 database. LOVD has the goal "to provide a flexible, freely available tool for Gene-centered collection and display of DNA variations" ( LOVD is available to all investigators and is considerably easy to use. Patients with TGM1 mutations can be entered into our database completely anonymously. This will allow future investigators who discover TGM1 gene mutations to deposit them in a comprehensive list.

Finally, our group built a computer-generated three-dimensional model of the transglutaminase-1 enzyme. This model is a well-educated guess at the actual structure and was based on the known structure of a similar enzyme, factor XIIIa. The model allowed us to view the enzyme on the computer and assess the enzyme's different parts, which are called domains, including the catalytic core. With this model, we observed that a lot of the mutations that cause amino acid changes occur at the boundaries between the different domains of the transglutaminase-1 enzyme. Most of these mutations changed the amino acid arginine to another amino acid.

In summary, we investigated ARCI by reporting mutations in TGM1, reviewing the published literature, creating a TGM1 database, and modeling the enzyme. Further investigations on human skin cells and animal models, which mimic ARCI, will elucidate the cellular events that lead to this rare type of ichthyosis. Classification of mutations will also help with prenatal diagnosis. Greater understanding, achieved through these types of studies and others, may lead to novel treatments.

Matthew Herman is a researcher in the lab of Dr. Jorge Toro

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