Scientists at Sanford Burnham Prebys Medical Discovery Institute and international collaborators announced on Mar. 24 the identification of a new genetic disease characterized by premature aging and deficits in brain function.
The discovery is significant because it marks the first time genome sequencing has been combined with cellular reprogramming to pinpoint a specific gene mutation responsible for symptoms observed in patients with this newly defined condition. The findings were published on March 19 in Nature Communications.
Senior and corresponding author Su-Chun Zhang, MD, PhD, said, "Our collaborator identified a family of patients whose teenaged members had whitening hairs and other characteristics associated with premature aging conditions known as progeria syndromes." Zhang continued, "Cognitive functions are often well-preserved in these conditions, however, so it was clear from the patients' progressive loss of motor skills and neurological and intellectual deficits that this was an unknown disease."
The team traced the disorder to a mutation in the IVNS1ABP gene using genome sequencing and mapping recessive traits. Fang Yuan, PhD, staff scientist at Sanford Burnham Prebys and first author of the study, said, "Relatively little research has been done on this gene and protein, and no one has ever linked them to the biology of aging, premature aging diseases or neuropathy." Yuan added: "It was a mystery in many ways, and one we were determined to solve."
To understand how this mutation affects cells, researchers reprogrammed skin cells from affected patients into induced pluripotent stem cells that retained the IVNS1ABP mutation. These precursor neural progenitor cells allowed experiments showing slower growth compared to controls from an unaffected sibling. Zhang said: "Under the microscope, we found that the patient-derived cells with the mutation grow much slower compared to the control group reprogrammed from a sibling without the disease."
Further analysis indicated these cells entered cellular senescence due to DNA damage occurring during cell division—a process severe enough to cause cell death according to follow-up experiments described by Yuan. Researchers identified actin-related proteins as likely contributors; mutant actin filaments formed irregular structures during cell division leading to further genomic harm.
Zhang explained: "During cell division, the actin filament needs to form an anchoring structure... But in mutant cells...the altered actin forms a shrunken and irregularly shaped ring." Yuan added: "When these actin dynamics are altered, the cell cannot perform cell division at the right time and in the right place." The team demonstrated that chemicals stabilizing actin could improve normal cell division rates.
Zhang concluded: "This research highlights the potential of using cellular reprogramming and patient-derived stem cell models to study rare and unknown diseases." Yuan noted: "And we already showed that if we correct some of steps in molecular processes...we can fix some defects at least in cellular model." The researchers plan further studies using animal models.
