In a finding that may have broader implications for understanding kidney disorders, genetics researchers at The Children's Hospital of Philadelphia have identified a second gene that gives rise to Alagille syndrome, a genetic developmental disease that affects multiple organs. The Children's Hospital team previously discovered the first gene associated with this disease.
The researchers found that mutations in the NOTCH2 gene were linked to kidney abnormalities in patients and families. "While Alagille syndrome is relatively rare, organ diseases are not rare, and our findings suggest that genes on this biological pathway may have a broader role in kidney disorders," said study leader Nancy B. Spinner, Ph.D., a geneticist at The Children's Hospital of Philadelphia.
The study appears in the July issue of the American Journal of Human Genetics.
Dr. Spinner led the Children's Hospital team that identified mutations in the JAG1 gene as a cause of Alagille syndrome in 1997. Like the NOTCH2 gene analyzed in the current study, JAG1 is part of a signaling pathway that governs important processes in early human development.
Alagille syndrome, estimated to occur in one in 20,000 individuals, is a complex disorder, primarily affecting the liver, heart, eyes, face and skeleton. Some patients with Alagille syndrome have very mild symptoms or isolated problems, while others may have severe, life-threatening heart or liver defects.
Both the JAG1 and the NOTCH2 genes participate in the Notch signaling pathway. JAG1 codes for the ligand Jagged1, a signaling protein that triggers receptors in the pathway. The NOTCH2 gene codes for Notch2, which is one of those receptors. The pathway as a whole is active during embryonic development, and transmits signals to cells to develop into specialized organs. Mutations in those genes are thought to disrupt normal development, by, for instance, causing the defective bile ducts found in the livers of many patients with Alagille syndrome.
"Ligands and receptors are like keys and locks," said Dr. Spinner. "If either one is defective, it may interfere with normal growth and development."
Dr. Spinner's team previously determined that 94 percent of patients diagnosed with Alagille syndrome had mutations in the JAG1 gene. In the current study, they analyzed 11 patients with Alagille syndrome who did not have the JAG1 mutation, and found that two of them had mutations in NOTCH2. Furthermore, the patients had three family members, all mildly affected, who also had the same mutation. All five individuals had kidney disease.
Because their study identified only two families with NOTCH2 mutations, said Dr. Spinner, it is not definitive in establishing that those mutations cause a distinct variety of Alagille syndrome. However, it is the first study to report that mutations in the NOTCH2 gene cause human disease. Dr. Spinner is planning further studies to better characterize the role of NOTCH2 mutations and the Notch signaling pathway in the wider population of patients with kidney disorders.
She also will investigate liver involvement in Alagille syndrome under the Rare Diseases Clinical Research Network, recently established by the National Institutes of Health. "Part of the rationale for this research network is that, collectively, relatively rare diseases added together constitute a significant portion of the population," said David A. Piccoli, M.D., chief of Gastroenterology and Nutrition at Children's Hospital and a co-author of the study. "Another rationale is that studying relatively rare diseases may offer insights into more common diseases and into health in general."
John Ascenzi | EurekAlert!
Polymers Based on Boron?
18.01.2018 | Julius-Maximilians-Universität Würzburg
Bioengineered soft microfibers improve T-cell production
18.01.2018 | Columbia University School of Engineering and Applied Science
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
18.01.2018 | Life Sciences
18.01.2018 | Life Sciences
18.01.2018 | Earth Sciences