A collaborative research project led in part by the Indiana Biosciences Research Institute (IBRI) has resulted in the first description of a new monogenic disease, named, “DHPS Deficiency.”

Our study identified the first human mutations in the deoxyhypusine synthase (DHPS) gene and described certain cellular effects that result from these mutations. My lab worked closely with Dr. Wendy Chung, Kennedy Family Professor of Pediatrics in Medicine at Columbia University Vagelos College of Physicians and Surgeons, and her lab, as well as a large group of collaborating physicians and scientists to realize this breakthrough.

From the moment the initial scientific observations were made, as a team we knew that the study needed to be completed as quickly as possible. We were collectively motivated to begin to provide answers to those individuals and families affected by the disease as well as to tell the scientific community about this landmark discovery.

The study, which began in mid-2017, identified five people, mostly children, from four unrelated families, who all developed similar if not identical symptoms of unknown cause until the identification of the common DHPS mutations. DHPS is an enzyme that is essential for the production of the unique amino acid, hypusine, which works in every cell of the body to help make proteins. The function of DHPS is essential for life. The mutations we identified in the patients cause a reduction in DHPS enzyme activity, which leads to clinical symptoms that include neurodevelopmental delay and seizures.

The study was published Jan. 17, 2019, in the American Journal of Human Genetics. The article is entitled, “Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.”

Breakthrough will help find others affected

This work is significant not only because it is the first description of a new monogenic disease, but as a result of the study’s publication, researchers will be able to find other affected individuals and families from around the world. We can also now direct our research toward finding an effective treatment so that one day, testing for DHPS Deficiency can be included when infants are screened for genetic diseases.

As with so many rare genetic diseases, the more we as researchers can collaborate to advance the understanding of how these diseases occur and affect the body, the closer we will come to translating these findings into therapies that reduce the burden of disease for all patients.

In addition to Dr. Chung and me, the large collaborative team included scientists and medical professionals from Columbia University Irving Medical Center, the Indiana Biosciences Research Institute (IBRI), Indiana University School of Medicine, NYU Langone Health, GeneDx, University of Calgary, Duke University Medical Center, Ann & Robert H. Lurie Children’s Hospital  of Chicago, Feinberg School of Medicine at Northwestern University and the National Institutes of Health (NIH).

New foundation supports research

The families affected by this disease were very supportive of our work, which was essential to the success of the study. In the relatively short time Dr. Chung and I have been working together, the DHPS Foundation was also formed. The Foundation continues to help get the word out and supports other families living with this disease. More at www.dhpsfoundation.org.

Excitingly, as a result of this work, Dr. Chung and I have also become involved in a larger research consortium that includes groups from around the world that are studying rare disorders that occur because of mutations in genes related to DHPS. It is our hope that working together to understand the similarities and differences between these disorders will bring us closer to findings ways to treat or even prevent the debilitating effects that occur from these human genetic diseases.

Teresa Mastracci, Ph.D., leads the IBRI’s Regenerative Medicine and Metabolic Biology group, which is part of the IBRI’s Diabetes Center. The IBRI is a non-profit, independent applied research institute formed in 2013 to bring together companies and universities to work collaboratively on interrelated health issues that are of both global significance and have a disproportionate impact on Indiana residents—diabetes, metabolic disease and poor nutrition, and related health data science and analytics. Our motto is Discovery With Purpose, reflecting our commitment to the translation of scientific discovery into improved outcomes. http://indianabiosciences.org