Gene Mutations in Rare Skin Disorder Identified, Paving the Way for Better Treatment

A commonly used medication can help treat a skin disorder called Ichthyosis, according to a research by Yale scientists. The research team also identified a genetic mutation that causes the skin disorder. Ichthyosis is a rare skin disorder that affects about one in 200,000 people. Ichthyosis is characterized by dry, scaly and thickened skin. Some topical medications can help treat the disease but there is no cure.

Genes Linked to Ichthyosis

A research team from Yale University conducted a study to understand the underlying causes of such disorders better. The team analyzed the genes of individuals affected with ichthyosis.

Initially, the research team sequenced exomes (protein-coding portions of the genome) to uncover the potential new causes of ichthyosis. They identified mutations in the gene KDSR that causes Ichthyosis. Mutations in the gene KDSR (3-Ketodihydrosphingosine Reductase) can prevent the skin from producing ceramides ( naturally generated fat molecules that seal the skin and protect it from water loss). Ceramides are used as a component in most of the commonly used moisturizers and cosmetics.

“Mutations underlying most types of ichthyosis have been identified, but roughly 15% of cases have unexplained origins,” said, Dr. Keith Choate, associate professor of dermatology and senior author.

Mutation in KDSR Gene

All the study participants with ichthyosis had a KDSR mutation that might have been missed by standard analysis methods. Three of the participants had a silent substitution, which is usually considered harmless. However, this particular mutation was demonstrated by the team to disrupt splicing (gene copies that are translated into proteins).

The research team found that some participants had observable mutations in both copies of the gene (one inherited from each parent). Initially, two participants seemed to show only one mutation. This led the research team to look more closely. Both the participants shared a common benign variation in the KDSR gene. This appeared more frequently in the population to be disease-causing, but rare in coincidental observation. This was a clue that these individuals were likely to share another KDSR mutation, which causes ichthyosis, but was not revealed by exome sequencing.

Genetic sequencing of the entire genome of one study participant validated the hypothesis of the study. "This underscores the importance of comprehensively investigating unsolved genetic diseases," said, Dr. Lynn Boyden of the Yale Department of Genetics, lead author on the study.

Common Acne Medication can Treat Ichthyosis

The research team also found that a commonly used acne medication called isotretinoin (Accutane), can counteract the effect of the mutations. Isotretinoin allows the skin to employ a different biological pathway to produce ceramides and prevent skin disorder.

"In both patients who’ve utilized it, the medication has cured the disease," said Choate.

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The findings of the study highlight the central role of ceramides in skin health and their importance as a common ingredient in most of moisturizers and other cosmetic products.

What is Ichthyosis?

Ichthyosis is a skin disorder, characterized by dry and thickened skin. There are more than 20 varieties of ichthyosis, including inherited and acquired forms. Some of the inherited forms of ichthyosis are ichthyosis vulgaris, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis and keratinopathic Ichthyosis. Ichthyosis vulgaris is the most common inherited disorder. Mutation in the filaggrin gene (FLG) is the cause of moderate or severe ichthyosis vulgaris.

Reference:

1. What is ichthyosis? - (http://www.dermnetnz.org/topics/ichthyosis/)
2. Mutations in Gene Cause Ichthyosis Vulgaris - (https://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2007/iv_filaggrin.asp)

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Source-Medindia