Although there are just a few families in the world known to carry the causative mutations, researchers speculate that the condition, called intractable diarrhea of infancy syndrome (IDIS), may share disease-causing mechanisms with other gastrointestinal illnesses that affect millions of people - such as irritable bowel or Crohn's disease. There are currently no treatments for IDIS other than nutritional and caloric support to make up for the impaired food absorption caused by frequent diarrhea. Typically, individuals with IDIS who survive infancy experience fewer symptoms as they get older, but their condition is never normal.

Though it was first described in 1968, very little was known about IDIS before the clinical team's lead researcher, began studying it in 2000. As it has only been identified in seven families of Iraqi-Jewish descent, the disease was simply too obscure to garner much attention from the medical science community. At the time, the only established information was that IDIS is a single-gene mediated recessive trait - meaning a child will show symptoms if they receive a mutated copy of the causative gene from both parents.

Hoping to gain fresh insights into the illness through modern analytical techniques, researchers started by performing sequencing of all known gene sequences on samples they had collected from their IDIS patients.

Unfortunately, the results were far from clear-cut. All eight individuals did indeed carry mutations that are not found in healthy individuals from the same region, but these variations were found to be in apparently noncoding sequences - stretches of DNA that don't get translated into a protein. More specifically, the patients (who represented each of the seven affected families) harbored deletions in both copies of a previously unstudied noncoding region on chromosome 16.

Noncoding sequences make up about 99% of the human genome and, despite their prevalence, are also the source of most unresolved questions about genetics. Once thought be to mere "junk' DNA, scientists now know that some noncoding regions have important regulatory functions, yet digging deeper into the roles of these regions has always been much more challenging than studying DNA that codes for a protein.

First, the geneticists used their world-leading mouse model platform to confirm that the chromosome 16 region is indeed a regulatory sequence involved in the development of the gastrointestinal system. When they engineered a lineage of mice with chromosomal deletions equivalent to those of human patients, the infant animals displayed diarrhea. These findings provided evidence that the noncoding sequence - which they termed the intestine-critical region (ICR) - is the cause of the disease. However, they still did not know what the regulatory sequence was actually regulating.

After years of painstaking experimentation, the authors were able to determine that the ICR controls expression of a previously unknown nearby gene, now called Percc1.

"It took years of gathering data from our mice before we uncovered that there was a gene very close to the deletion that we just happened to not be able to observe before," said the senior author. The team found that Percc1 is present in all mammals and most vertebrates, thus establishing that it has been in animal genomes for eons. But because the protein this gene encodes is almost completely unlike any known proteins - in both sequence and structure - it was easily overlooked in gene mapping studies until the team started closely examining its chromosomal region.

Looking back at their human sequence data after this discovery, the authors saw that both types of ICR deletions carried in IDIS families prevent any Percc1 protein from being made. So, to formally connect the dots and prove that a lack of Percc1 gene expression is the sole cause of IDIS, they bred a new lineage of mice that had no genetic abnormalities other than a deleted Percc1 gene. Immediately after birth, the mutant mice experienced severe, chronic diarrhea that perfectly mirrored the disease progression of humans with IDIS. "That puts a nail in the coffin that yes, that must be what causes the condition because mice have the same exact symptoms," explained the author.

After establishing what goes wrong when the enigmatic Percc1 protein is missing, the prolific scientists conducted one last round of experiments to provide a rough sketch of what it does under normal circumstances. Using their mouse model and human stem cells, the scientists showed that the Percc1 protein is expressed in (and necessary to the proper functioning of) a very small group of hormone-producing gastrointestinal cells. Through chemical signaling, these cells appear to mediate many processes, including intestinal motility, glucose uptake, and triggering the sense of satiety.

https://newscenter.lbl.gov/2019/07/10/deadly-disease-gene-revealed/

https://www.nature.com/articles/s41586-019-1312-2