Novel gene mutation linked to rare premature-aging syndrome

UT Southwestern researchers have discovered a new form of progeria, a rare premature-aging syndrome, in a man from Malaysia and traced its cause to a novel gene mutation. The finding, reported in the Journal of Clinical Investigation, could lead to new therapies for more common conditions that share features with this ultra-rare disorder.

We realized that this is not like the progeroid syndromes we have seen in the past. It is a completely new subtype. We wanted to see whether we could find the gene behind it."

Abhimanyu Garg, M.D., Study Leader, Professor of Internal Medicine at UTSW, Section Chief of Nutrition and Metabolic Diseases in the Division of Endocrinology, and Director of Metabolic Diseases in the Center for Human Nutrition

Dr. Garg explained that colleagues in Malaysia had encountered a patient of Chinese descent with a highly unusual combination of physical characteristics. The 21-year-old male was 3.8 feet tall, weighed 46 pounds, and had a head circumference of 21 inches, all below the lowest 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 severe dental crowding, as well as very low body fat – a condition known as lipodystrophy – and extremely poor vision.

Because Dr. Garg's lab focuses on lipodystrophy research and had previously discovered the genetic mutations behind a condition called mandibuloacral dysplasia (MAD), which the Malaysian researchers believed 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 the patient lacked mutations in either of the two genes linked to MAD.

Suspecting the patient might have an undiscovered condition, Dr. Garg and his collaborators scanned the entire genomes of the patient and his immediate family members for any unusual gene 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 power-generating organelles of cells.

To better understand its function in humans, the researchers grew skin cells from a sample derived from the patient and compared them to skin cells from healthy volunteers. Tests showed that the patient's cells consumed far more oxygen than the healthy cells and produced greater amounts of proteins related to oxygen metabolism. They also produced fewer proteins related to phospholipid metabolism, a process involved in the formation of body fat.

Further experiments showed that the mutant TOMM7 protein from the patient didn't interact well with other proteins that form the mitochondrial pore complex. This functional defect, Dr. Garg said, could limit the transportation of proteins through the pore, pointing to a mechanism for the patient's symptoms.

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

"We don't know what his life span may be, but based on what we know about his sister, he may be at risk of premature death," he said. "I hope other scientists will take it to the next level and figure out a specific treatment that could save this patient from that fate."

Dr. Garg holds the Distinguished Chair in Human Nutrition Research.