Genetic mutations link rare skin disorder and non-alcoholic fatty liver disease

Reviewed by Kate Anderton, B.Sc. (Editor)Jul 25 2019

Fatty liver disease is often associated with alcoholism, but more than a third of Americans have fatty livers despite moderate or absent alcohol consumption. They suffer from non-alcoholic fatty liver disease, a condition that can lead to cirrhosis, liver cancer and liver failure. Many patients require liver transplants to beat the disorder.

Now researchers led by Jouni Uitto, MD, PhD, Professor of Dermatology and Cutaneous Biology at Thomas Jefferson University report mutations in a gene called ABHD5 involved in non-alcoholic fatty liver disease. The finding provides a genetic basis for the condition.

The scientists made the discovery not by studying the liver, but the skin. Dr. Uitto and colleagues were investigating a condition called Chanarin-Dorfman syndrome, a severe but rare skin disorder, in several families from Iran. Patients with Chanarin-Dorfman syndrome develop dry, reddish and scaly skin shortly after birth. Later on in life, they acquire abnormally large and fatty livers.

First author Leila Youssefian in Dr. Uitto's lab, and others sequenced the genomes of six families. Several members of each family had non-alcoholic fatty liver disease, but didn't have any skin symptoms. Although the researchers knew mutations in ABHD5 lead to Chanarin-Dorfman syndrome, the analysis helped to uncover a surprising link.

It turns out that if you have one mutated copy of the ABHD5 gene you get the liver disease only. But, if you have mutations in both copies, then you get the liver disease plus Chanarin-Dorfman syndrome."

Jouni Uitto, MD, PhD, Professor of Dermatology and Cutaneous Biology, Thomas Jefferson University

The scientists confirmed the result by sequencing the genomes of members of a large Italian family with a family history of the liver disease. They found that the nine family members with non-alcoholic fatty liver disease had one mutated copy of the ABHD5 gene. The discovery indicates that mutations in one copy of ABHD5 predispose individuals to non-alcoholic fatty liver disease. The findings also suggest that parents of children with Chanarin-Dorfman syndrome should get screened for mutations in ABHD5.

Dr. Uitto and his team's finding is the first demonstration of a heritable mutation that leads to non-alcoholic fatty liver disease, but further analyses revealed there are likely many more genes in addition to ABHD5 that underlie the condition.

The research shows the value of studying rare diseases, conditions in which there are less than 200,000 affected individuals in the U.S. The researchers were able to make the connection between cases of non-alcoholic fatty liver disease and the skin disorder Chanarin-Dorfman syndrome because they study a rare disease.

"Studying a rare, heritable disease such as Chanarin-Dorfman syndrome, can be very helpful in identifying conditions which are much more prevalent, like in the case of non-alcoholic fatty liver disease," says Dr. Uitto.

Additionally, "the link between non-alcoholic fatty liver disease and scaly skin diseases such as Chanarin-Dorfman syndrome highlights the importance of regulated lipid metabolism in skin physiology," says Dr. Uitto. "In fact, there are several heritable disorders manifesting with dry and scaly skin associated with mutations in genes like ABHD5 that are involved in lipid metabolism. Identification of such genes and specific mutations now form the basis for ongoing studies attempting to develop treatment for these often devastating skin disorders."