August 03, 2012
By C.J. Janovy
|Left to right: Robert De Lisle, Glen Andrews and Jim Geiser|
Zinc is an essential element for human health — people who don't get enough of it can have stunted growth, immune-system dysfunctions, hair loss, chronic diarrhea, severe dermatitis, vision problems, reproductive problems, psychoses and other mental disorders.
Among the most drastic consequences of zinc deficiency is a rare genetic disease known as acrodermatitis enteropathica (AE), which occurs in about one out of 500,000 people. Symptoms develop in infants and progress to include all of the problems associated with a lack of zinc — and patients will die unless excess zinc is added to their diets.
Scientists know of 24 genes that help the body absorb, store and excrete zinc. Among these is the zinc transporter known as Zip4 — which is mutated in people who have AE. Less well-understood is how the loss of Zip4 causes AE in humans and how the disease progresses. Now, however, a team of KU Medical Center researchers has created a mouse model with the human disease, which will allow scientists to more effectively study the disease and potentially find treatments.
Glen K. Andrews, Ph.D., University Distinguished Professor in the Department of Biochemistry and Molecular Biology, along with senior research associate Jim Geiser, Robert C. De Lisle, Ph.D., associate professor of anatomy and cell biology and Koen Venken, Ph.D., a postdoctoral fellow at Baylor College of Medicine, recently published their findings in PLoS Genetics.
Andrews and his team generated mice in which the Zip4 gene could be deleted on command. They were then able to see that Zip4 in the intestine is essential for developing enterocytes — the cells in the lining of the small intestine that are responsible for digesting and absorbing nutrients. "The absence of Zip4 in the intestine in mice closely mimics the AE phenotype in humans," Andrews explains. "When the Zip4 gene in the absorptive cells was deleted, we saw rapid wasting and death unless we gave the mice additional dietary zinc."
In particular, Andrews says, the absence of Zip4 caused a reprogramming of Paneth cells in the intestine.
"Paneth cells are specialized cells that have a very specific location and function. In the small intestine there are protrusions out into the lumen called villi, and these protrusions are lined with cells called enterocytes that absorb all the nutrients," Andrews explains. "At the base of each protrusion is a crypt from which all of the intestine stem cells originate. These cells normally divide rapidly creating new enterocytes for the intestinal lining every three to four days. The Paneth cells are located at the bottom of the crypt and function to fight infections and provide growth factors to support stem cell development. They are an important part of the stem cell niche in the intestine." After the Zip4 gene was deleted, zinc in Paneth cells quickly disappeared. Soon the Paneth cells themselves stopped working properly.
"When the Zip4 is gone it disrupts the stem cell niche, and when the stem cells don't divide properly the intestine can't absorb foods properly. That's what we discovered," Andrews says. "That affects the whole animal — it loses zinc, fails to absorb nutrients, wastes away and dies."
The discovery is exciting for several reasons. "AE is a very rare disease, so we had no previous proof that Zip4 expression in the intestine was crucial because these people had no Zip4 anywhere," Andrews says. "It wasn't clear how the disease progresses in its very early stages, so this helps define a mechanism of that disease."
The effect of the gene mutation on the Paneth cell and its effect on the intestine itself had never been understood, Andrews adds. "The other thing we discovered is that when you lose this zinc transporter, there was also a change in the metabolism of iron, copper and manganese as well as zinc — that was a surprising finding. We also now have more details on how the gene mutation affects the intestinal lining, changes energy metabolism and suppresses protein synthesis."
Next, Andrews says, his team will work on reversing the progression of the disease. Now that he knows more about the mechanisms of AE, Andrews says, "We're working on ways to reverse that phenotype so that the intestine can become functioning again."