Researchers at Vanderbilt University, the University of Arizona and Phoenix Children’s Hospital have discovered what triggers a rare but devastating diarrheal disease in newborns that is fatal without intravenous feeding or intestinal transplant.
The report, published recently in the Journal of Clinical Investigation, could lead to ways to improve the symptoms of patients with the condition known as microvillus inclusion disease (MVID), and to a better understanding of other gastrointestinal disorders in newborns.
“I think it’s going to change how we view dealing with infants with these early life diarrheas,” said Vanderbilt’s James Goldenring, M.D., Ph.D., the Paul W. Sanger Professor of Experimental Surgery and co-senior author with Mitchell Shub, M.D., of the University of Arizona and Phoenix Children’s Hospital.
In 2008 Shub and University of Arizona colleague Robert Erickson, M.D., identified the genetic mutation responsible for MVID among the Navajo in the southwestern United States, where it occurs at a relatively high incidence of one case per 12,000 births.
The current study, led by Vanderbilt M.D./Ph.D. student and first author Byron Knowles, Ph.D., determined how the mutation disrupts the function of a protein called myosin Vb (MYO5B), which is essential for repairing and maintaining the microvilli that form the small intestine’s epithelial lining.
Without functional protein, the tips of the villi, which normally absorb nutrients, become “leaky,” causing unremitting diarrhea within days after birth.
“There’s clearly a spectrum” of these diarrheal disorders, said Knowles, a medical student in Vanderbilt’s Medical Scientist Training Program who defended his Ph.D. in Cell & Developmental Biology last month.
“Figuring out why the disease at the far end of the spectrum is so severe may give us a way forward to figure out how to manage patients” with less severe disease, he said.
That’s why genetic screening for mutations “makes a lot of sense” in evaluating children with diarrhea of unknown causes, agreed Goldenring, professor of Surgery and of Cell & Developmental Biology and co-director of the Epithelial Biology Center, who mentored Knowles.
“We’re going to find certain of these diarrhea syndromes where we can intervene with a drug or a treatment,” he said.
Knowles created a model of the disease by reducing the expression of the MYO5B gene in cells grown in culture. These cells resembled those from MVID patients with the mutation. “They show similar abnormalities at their apical surfaces,” Goldenring said.
A native of the Bahamas, Knowles has another, more personal connection to the subject. His fiancée, Rachel Ruiz, M.D., a first-year resident in Pediatrics at the Monroe Carell Jr. Children’s Hospital at Vanderbilt, did volunteer work for the Navajo Nation in 2012.
Other co-authors of the study were Joseph Roland, Ph.D., Moorthy Krishnan, Ph.D., Matthew Tyska, Ph.D., Lynne LaPierre, Ph.D., all of Vanderbilt, and Paul Dickman, M.D., of Phoenix Children’s Hospital.
The researchers acknowledged the help of the families of the Navajo patients, who allowed archived tissue samples from their children to be studied, as well as the Phoenix Children’s Hospital gastroenterology team. The study was supported by National Institutes of Health grants DK070856, CA068485, DK020593, DK058404 and HD015052.
