UTSW researchers discover rare premature aging syndrome

DALLAS – December 7, 2022 – Researchers at UT Southwestern have discovered a new form of progeria, a rare premature aging syndrome, in a Malaysian man and traced its cause to a new genetic mutation. The discovery, reported in the Clinical Investigation Journalcould lead to new therapies for more common conditions that share characteristics with this ultra-rare disorder.

“We realized it wasn’t like the progeroid syndromes we’ve seen in the past. This is a whole new subtype,” said study leader Abhimanyu Garg, MD, professor of internal medicine at UTSW, section chief of nutrition and metabolic diseases in the division of endocrinology and director of metabolic diseases at the Center for Human Nutrition. “We wanted to see if we could find the gene behind it.”

Dr Garg explained that colleagues in Malaysia had come across a patient of Chinese descent with a very unusual combination of physical characteristics. The 21-year-old was 3.8 feet tall, weighed 46 pounds and had a head circumference of 21 inches, all below the bottom 3% of the general population. He also had a unique set of facial features, with a pointed nose, thin lips, a small lower jaw and heavy dental crowding, as well as very low body fat – a condition known as lipodystrophy – and vision. extremely bad.

Because Dr. Garg’s lab focuses on lipodystrophy research and had previously discovered the genetic mutations causing a condition called mandibuloacral dysplasia (MAD), which Malaysian researchers thought this patient had, they sent Dr. Garg the patient’s blood samples to confirm their tentative diagnosis. However, when Dr. Garg and his colleagues performed genetic testing, they found that the patient did not have mutations in either of the two MAD-linked genes.

Suspecting that the patient might have an undiscovered disease, Dr. Garg and his collaborators scanned the entire genome of the patient and his immediate family members for unusual genetic variants. They quickly narrowed their search to a single gene known as TOMM7.

From animal studies, this gene was known to produce a protein that comes together in a complex with related proteins to form a pore in the outer membrane of mitochondria, the energy-generating organelles of cells.

To better understand its function in humans, the researchers cultured skin cells from a sample from the patient and compared them to skin cells from healthy volunteers. The tests showed that the patient’s cells consumed much more oxygen than healthy cells and produced greater amounts of proteins related to oxygen metabolism. They also produced less protein related to phospholipid metabolism, a process involved in the formation of body fat.

Further experiments showed that the mutant TOMM7 the patient’s protein did not interact well with the other proteins that form the mitochondrial pore complex. This functional defect, Dr. Garg said, could limit protein transport through the pore, pointing to a mechanism for the patient’s symptoms.

Dr Garg said more common variants of this gene could help explain population-wide differences in exaggerated characteristics in this patient, such as height, jaw size, body fat and vision. Additionally, since the patient had an older sister who appeared to have the same genetic syndrome and who died at age 10, further research into this genetic variant could clarify the genetic factors that affect aging – and could also eventually lead to a cure for that individual, who could be in danger, Dr. Garg said.

“We don’t know what his lifespan may be, but from what we know of his sister, he may die prematurely,” he said. “I hope other scientists will take it to the next level and find a specific treatment that could save this patient from this fate.”

Dr. Garg holds the Chair of Excellence in Human Nutrition Research.

Other researchers who contributed to this study include Adwait Amod Sathe, Chao Xing, Anil K. Agarwal and Prashant Mishra of UTSW; Yanqiu Shao of UTSW and Southern Methodist University; Wee-Teik Keng from Kuala Lumpur Hospital in Malaysia; Zhenkang Chen, Nicholas P. Lesner, and Claire B. Llamas of the UT Southwestern Children’s Medical Center Research Institute; and Pavithira Devi Kailasam from Pakar Sultanah Fatimah Hospital in Malaysia.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 researchers from the Howard Hughes Medical Institute. Full-time faculty of more than 2,900 are responsible for groundbreaking medical advances and committed to rapidly translating scientific research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 inpatients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits annually.