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From left, Sam McBrayer, Ph.D., Assistant Professor in Children\u2019s Medical Center Research Institute at UT\u00a0Southwestern (CRI), with study first authors and graduate students Haocheng Li, B.S., and Alex Sternisha, M.D., Ph.D., in the CRI Moody Flow Cytometry Shared Facility.\u202f<\/p>\n
DALLAS \u2013 July 16, 2026 \u2013 Scientists at Children\u2019s Medical Center Research Institute at UT\u00a0Southwestern (CRI)<\/a> have discovered why babies born with a rare inborn error of metabolism, called GPT2 deficiency, suffer from severe neurological impairment, according to research published in Science<\/a>.<\/p>\n Using their newly developed biosensor to track essential metabolite alpha-ketoglutarate (\u03b1KG), researchers found that mitochondrial enzyme GPT2 and transporter protein SLC25A11 work together to control production and transport of \u03b1KG from the mitochondria to the nucleus.<\/p>\n This artist rendering depicts the production and transfer of \u03b1KG from the mitochondrial matrix to the nucleocytosolic compartment by sequential activities of GPT2 and SLC25A11. (Illustration credit: Melissa Logies for CRI)<\/p>\n Since \u03b1KG is essential to unwind DNA for gene transcription, this new research suggests \u03b1KG supplementation at birth might help diminish disease progression, according to study leader Samuel McBrayer, Ph.D.<\/a>, Assistant Professor at CRI and of Pediatrics<\/a>.<\/p>\n \u201cGPT2 is expressed throughout the body, so it was difficult to understand why this enzyme would have a special role in the brain,\u201d Dr. McBrayer said. \u201cThe disruption of GPT2 activity causes substantial changes in DNA structure, most profoundly in brain cells, which dysregulates many important genes that must turn on during brain development.\u201d<\/p>\n Based on this insight, Dr. McBrayer collaborated with Eric\u00a0M.\u00a0Morrow, M.D., Ph.D.<\/a>, Mencoff Family Professor of Biology at Brown University, whose lab studies GPT2 deficiency and has created a mouse model to investigate the inborn error of metabolism.<\/p>\n More than a decade ago, Dr. Morrow initially characterized metabolic aspects of GPT2 deficiency with the help of Ralph J. DeBerardinis, M.D., Ph.D.<\/a>, Director of the CRI Genetic and Metabolic Disease Program<\/a> and the Eugene McDermott Center for Human Growth and Development<\/a>\u00a0at UT Southwestern.<\/p>\n Using Dr. Morrow\u2019s model, scientists found that by supplementing \u03b1KG from birth, newborn mice lacking the Gpt2 enzyme maintained their body weight, one mortality marker of the disease.<\/p>\n \u201cWe are really excited\u00a0about the possibility of developing treatments, such as potentially dietary supplements, that will help patients,\u201d Dr. Morrow said. \u201cThe discoveries in this paper provide\u00a0important new insights on mechanisms, and we will continue to test these treatments in animal\u00a0studies.\u201d<\/p>\n Scientists previously didn\u2019t understand how the pool of nuclear \u03b1KG was regulated. Study first author Alex Sternisha, M.D., Ph.D., a former graduate student in the McBrayer Lab, built a biosensor using a protein from cyanobacteria to examine what creates, transports, or consumes \u03b1KG.<\/p>\n \u201cCyanobacteria evolved this elegant mechanism to sense \u03b1KG because it\u2019s so important for their metabolism,\u201d Dr. Sternisha said. \u201cWe took a transcription factor that recognizes \u03b1KG from cyanobacteria, modified it to function in human cells, and linked its activity to expression of a green fluorescent protein so that we could monitor \u03b1KG levels in the nucleus of a living human cell.\u201d<\/p>\n Dr. McBrayer said \u03b1KG plays a dual role in cell metabolism. In addition to being part of the mitochondrial TCA cycle \u2013 a series of chemical reactions used to produce energy in the cell \u2013\u00a0it\u2019s also used by chromatin in the nucleus to control how tightly DNA is compacted.<\/p>\n Researchers, including co-first author Haocheng Li, B.S., found that if the GPT2 enzyme doesn\u2019t produce \u03b1KG in the mitochondria or if the SLC25A11 protein doesn\u2019t transport it to the cytosol, then not enough \u03b1KG diffuses into a cell\u2019s nucleus to support DNA unwinding, affecting DNA access and reducing gene activation.<\/p>\n The study also confirms the enzyme BCAT1, found in the cytosol, is an important \u03b1KG consumer and competes with other enzymes for available \u03b1KG.<\/p>\n Before now, scientists had only a partial understanding of why GPT2 deficiency leads to fewer synapses and weaker brain circuits. This contributes to neurological symptoms, including severe intellectual disabilities and progressive motor dysfunction, according to the National Organization for Rare Disorders<\/a>.<\/p>\n \u201cThere\u2019s a high degree of hope that we might be able to employ this treatment strategy in patients and really move the needle in that disease context,\u201d Dr. McBrayer said. \u201cTogether with Dr. Morrow\u2019s group, we nominated a metabolite supplementation strategy that might prevent some of the defects in neurodevelopment that afflict patients with GPT2 deficiency. We are currently analyzing this treatment strategy with the intent to advance it to clinical trial.\u201d<\/p>\n Dr. McBrayer is an Investigator in the Peter O\u2019Donnell Jr. Brain Institute<\/a> and a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center<\/a> at UT\u00a0Southwestern. He is also a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar. He was honored with a Distinguished Scientist Award in 2021 from the\u00a0Sontag Foundation.<\/p>\n Other study contributors include Dr. DeBerardinis, also Professor of Pediatrics and Director of the CRI Metabolomics Shared Facility<\/a>; Laura A. Banasyznski, Ph.D., Associate Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences<\/a>, CRI, and Obstetrics and Gynecology<\/a>; Michalis Agathocleous, Ph.D., Assistant Professor in CRI and Pediatrics; Thomas P. Mathews, Ph.D., Assistant Professor of Research in CRI and Pediatrics, and Assistant Director of the CRI Metabolomics Shared Facility; Chad A. Brautigam, Ph.D., Professor of Biophysics<\/a> and Microbiology<\/a>; Yoon Jung Kim, Ph.D., Assistant Professor of Research in CRI and Pediatrics; Javier Garcia-Bermudez, Ph.D., Assistant Professor in CRI and Pediatrics; Lin Xu, Ph.D., Assistant Professor of Health Data Science and Biostatistics<\/a> in the Peter O\u2019Donnell Jr. School of Public Health<\/a> and Pediatrics; and Ruth Gordillo, Ph.D., Associate Professor of Internal Medicine<\/a>.<\/p>\n This research was funded by the National Institutes of Health, the National Cancer Institute, the National Institute of Neurological Disorders and Strokes, the National Institute of General Medicine, the National Institute of General Medical Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development, the National Institute on Aging, a CPRIT grant, The Sontag Foundation, the Jonesville Foundation, The Nick Gonzales Foundation for Brain Tumor Research, a Burroughs Wellcome Fund Career Award for Medical Scientists, a Lubin Family Foundation Scholar Award, the Human Frontier Science Program, the American Cancer Society, a Pew-Stewart Scholars for Cancer Research award, The Welch Foundation, and the Howard Hughes Medical Institute Investigator Program.<\/p>\n Dr. DeBerardinis holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development and the Philip O\u2019Bryan Montgomery, Jr., M.D. Distinguished Chair in Developmental Biology and is a Sowell Family Scholar in Medical Research.<\/p>\n About CRI<\/p>\n Children\u2019s Medical Center Research Institute at UT\u00a0Southwestern (CRI) is a joint venture of UT\u00a0Southwestern Medical Center and Children\u2019s Medical Center Dallas. CRI\u2019s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology, and metabolism \u2013 relentless discovery toward the treatments of tomorrow. About UT\u00a0Southwestern Medical Center<\/p>\n UT\u00a0Southwestern, one of the nation\u2019s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution\u2019s faculty members have received six Nobel Prizes and include\u00a028\u00a0members of the National Academy of Sciences, 26 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of\u00a0nearly 3,400 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT\u00a0Southwestern physicians in more than 80 specialties care for more than 143,000 hospitalized patients, attend to more than 470,000 emergency room cases, and oversee nearly 5.3 million outpatient visits a year.<\/p>\n Related Stories<\/p>\n ![\"Mitochondrial](\"https:\/\/www.newsbeep.com\/us-tx\/wp-content\/uploads\/2026\/07\/mcbrayer-science-cover.jpg\")
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