Research reveals a genetic cause of fatal digestive disease in children

Nearly 10 years ago, a group of Israeli clinical researchers sent an email to geneticist Len Pennacchio of the Berkeley National Laboratory (Berkeley Lab) asking him to help solve the mystery of an illness rare hereditary that has caused extreme and sometimes fatal chronic diarrhea in children. .

Now, after an arduous survey odyssey that has broadened our understanding of the regulatory sequences of the human genome, the multinational scientific group has announced the discovery of the genetic explanation for this disease. Their results are published in Nature.

"By identifying the underlying gene, we have opened the door for the exploration of therapeutic targets," said Pennacchio, who has a dual mandate with Berkeley Lab's Environmental Genomics and Systems Biology Division. and the Joint Institute of Genome of the US Department of Energy (DOE). Although only a few families in the world are known to carry the mutations involved, Pennacchio and his co-authors speculate that the disease, called intractable child syndrome diarrhea (IDIS), may be badociated with mechanisms that cause millions of people – such as irritable bowel or Crohn's disease. At the moment, IDIS contains no other treatment other than nutritional and caloric support to compensate for the insufficient absorption of food caused by frequent diarrhea. Typically, people with IDIS who survive in childhood experience fewer symptoms as they age, but their health condition is never normal.

The other important result is that families now have an explanation for this disease, which has been plaguing children in the area for some time. "

Len A. Pennacchio, Berkeley Lab geneticist

Immerse yourself in a long-standing medical jigsaw

Although it was first described in 1968, very little was known about IDIS until the principal investigator of the clinical team, Yair Anikster, began to study it in 2000. As he was only identified in seven families of Iraqi-Jewish origin, the disease was simply too obscure to attract much attention from the medical scientific community. At the time, the only information established was that IDIS was a recessive trait induced by a single gene, which meant that a child would exhibit symptoms if he received a mutated copy of the gene. responsible for both parents.

In the hope of obtaining new information about the disease through modern badytical techniques, Anikster and a diverse group of colleagues began by sequencing all known gene sequences on samples taken from IDIS patients.

Unfortunately, the results were far from clear. The eight individuals actually carried mutations that are not found in healthy individuals from the same region, but these variations have been shown to be in apparently non-coding sequences – segments of DNA that do not are not translated into a protein. Specifically, the patients (who represented each of the seven affected families) harbored deletions in both copies of a non-coding region previously unstudied on chromosome 16.

Non-coding sequences make up about 99% of the human genome and, despite their prevalence, are also the source of most unresolved questions about genetics. Scientists once knew that some non-coding regions had important regulatory functions. Yet, deepening the role of these regions has always been much more difficult than studying the DNA encoding a protein.

Conscious of the need for an expert to establish a causal link between these deletions and IDIS, the group turned to the Pennacchio laboratory. The Pennacchio team has been studying genomic regulatory regions well since chromosome 16 sequencing for the flagship human genome project.

Find a hidden gene

First, geneticists used their world-leading mouse model platform to confirm that the chromosome 16 region was a regulatory sequence involved in the development of the gastrointestinal system. When they created a mouse line with chromosome deletions equivalent to those of human Anikster patients, the infants presented with diarrhea. These results provided evidence that the noncoding sequence – which they called the Critical Intestine Region (GIC) – is the cause of the disease. However, they still did not know what the regulations were.

After years of careful experimentation, the authors were able to determine that the ICR was controlling the expression of a previously unknown neighbor gene, now called Percc1.

"It took years of data collection from our mice before we discovered that there was a gene very close to the deletion that we simply could not observe before," Pennacchio said. He and his team discovered that Percc1 was present in all mammals and most vertebrates, establishing that it was in the animal genome for centuries. But since the protein that this gene codes encodes is totally different from all known proteins – both in sequence and in structure – gene mapping studies have easily ignored it until the The team begins to look closely at its chromosomal region.

After discovering the data of their human sequences after this discovery, the authors found that the two types of ICR deletions performed in IDIS families prevent the production of any Percc1 protein. Thus, to formally link the points and prove that a lack of expression of the Percc1 gene is the sole cause of IDIS, they created a new line of mice with no other genetic abnormalities. that a deleted Percc1 gene. Immediately after birth, the mutant mice exhibited severe chronic diarrhea that perfectly reflected the course of the disease in humans with IDIS. "It puts a nail in the coffin: yes, it must be the cause of the disease because the mice have exactly the same symptoms," said Pennacchio.

Coup of sending the next wave of research

After establishing what is wrong with the enigmatic Percc1 protein, prolific scientists conducted a final series of experiments to provide insight into what it does under normal circumstances. Using their mouse model and human stem cells, scientists have shown that the Percc1 protein is expressed in (and necessary for the proper functioning of) a very small group of gastrointestinal hormone-producing cells. Through chemical signaling, these cells appear to mediate many processes, including intestinal motility, glucose uptake, and triggering the feeling of satiety.

Anikster's clinical teams at Edmond and Lily Safra Children's Hospital, Sheba Medical Center and Sackler School of Medicine at Tel Aviv University plan to use their new knowledge. on the gene to study more closely the evolution of the disease over time. "The scientific journey was particularly long, difficult and full of surprises," he said. "We hope our discovery will pave the way for targeted treatment of this potentially life-threatening disease."

Meanwhile, Pennacchio's lab will continue to do what it does best.

"For 20 years, we have used the mouse as a powerful system to better understand not only the human genome, but also the functioning of all genomes," Pennacchio said. "At Berkeley Lab, we focus on providing the tools and expertise necessary to perform the complex and large-scale work that small institutions can not do on their own."