After 15 years of research, a team of researchers from Israel and the U.S. have identified a gene responsible for severe intestinal diseases in newborns

Congenital diarrhoeal disorders (CDDs) are rare hereditary diseases characterized by severe diarrhea, which start after the birth. Without proper treatment, the severe diarrhea can lead to dehydration and malnourishment, and may even be life-threatening.

These disorders may be caused by a variety of structural or functional defects in the digestive system. Because of their wide range, it is difficult to understand the genetic background behind the disorders.

Research groups from Tel Aviv University, the Sheba Medical Center, and the Weizmann Institute of Science, together with a team from the University of California, Berkeley studied the genetic background of CDDs in eight Israeli patients. Their expansive investigation culminated in the identification of the gene responsible for the disorder.

A regulatory fault

Numerous genetic diseases are caused by mutations in genetic segments that encode for proteins, termed exons. Most of our genome does not encode for proteins but rather, is composed of genetic sequences that have various regulatory functions.

The researchers began by determining the genetic sequence of the exons in the patients’ cells and compared them to those of healthy children, finding no mutations. Next, they decided to sequence the entire genome—including the non-coding, regulatory segments. The comparison of these sequences to the DNA of healthy children exposed a segment absent in the patients. The region of the missing segment, which the researchers termed ICR, was mutated in all eight patients, hinting at its involvement in the disease. The researchers also found that the ICR region was evolutionarily conserved among vertebrates, which is an indication of its importance. Furthermore, they found that the ICR is expressed in the digestive system during embryonic development, a fact which could indicate its function.

In order to show that the missing segment was indeed responsible for the disease, the researchers genetically engineered mice with a segment missing in the ICR region. These mice indeed suffered from the same symptoms that the disease caused in humans: Diarrhea developed at a very early age, they did not develop properly, and their survival rates were lower than that of their healthy siblings.

Subsequently, the researchers set out to identify the genes regulated by the ICR region. By analyzing expression patterns of different genetic sequences in mouse tissues, they found a segment in the genome whose expression depended on the ICR. It turned out that this segment, PERCC1, is a gene that encodes for a protein that was never previously described or studied. When the researchers genetically engineered mice with a mutation that impairs the production of PERCC1, these mice also suffered from the same symptoms as the human disease.

The researchers concluded that the ICR regulates the expression of PERCC1 in the digestive system during embryonic development and that the gene’s proper expression is crucial for healthy development.

15 שנים בחיפוש אחר גן יחיד. מימין: דורון לנצט, יאיר אניקסטר ולן פנקיו | צילומים: מכון ויצמן למדע, בי"ח שיבא, אונ' ברקלי

15 years in search of one gene. Right to left: Doron Lancet, Yair Anikster, and Len Pennacchio. Photography: The Weizmann institute, Sheba Medical Center, and University of California, Berkeley.

A long and winding road

This study joins others in the attempt to identify the genetic elements causing CDDs, and highlights the importance of regulatory segments in the proper development of the digestive system and in genetic diseases.

“The research took around 15 years, and ultimately, we achieved an important and interesting progress,” summarizes Prof. Doron Lancet, from the Department of Molecular Genetics at the Weizmann Institute of Science, who led the study together with Prof. Yair Anikster from Tel Aviv University and Sheba Medical Center, Len Pennacchio from the University of California, Berkeley, and research students Danit Oz-Levi, Tsviya Olender, and Ifat Bar-Joseph. “This progress enabled the identification of the mutation responsible for the disease and the gene that it regulates, which turned out to be an unfamiliar gene, about which nothing was known”.

Lancet notes that one of the challenges in the research was the gene’s surprising location. “The fact that we successfully connected regulatory regions and their relevant genes is a Weizmann Institute innovation. There has been a significant improvement it the ability to link regulatory regions in the genome to the genes which they regulate over the last years, and this is especially important in cases like this, in which the regulatory region is far from the region encoding for the gene”.

Will the successful identification of the cause of the disease now lead to drug development? Lancet, in response, is restrained, saying “The road to a drug is still very long and winding one.”