Scientists Discover New Genetic Disease Causing Premature Aging and Cognitive Deficits
Researchers have identified a new genetic disease characterized by premature aging and cognitive deficits, tracing it to a mutation in the IVNS1ABP gene. Using cellular reprogramming, they discovered the mutation causes cellular senescence and DNA damage during cell division through altered actin dynamics. The findings highlight the potential of patient-derived stem cell models to study rare diseases and identify potential treatment approaches.
Scientists have defined a new genetic disease marked by premature aging and deficits in brain function. The research team used genome sequencing combined with cellular reprogramming to identify the gene mutation responsible and study how it causes the symptoms observed in patients suffering from this newly discovered condition.
The investigators traced the disease to a mutation in the IVNS1ABP gene, which holds the instructional codes for building IVNS1ABP, an influenza virus non-structural protein-1 binding protein. 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.
To explore the effects of this gene mutation, the scientists acquired samples of skin cells from the affected patients and reprogrammed them into induced pluripotent stem cells. These cells were coaxed into a state that is more mature than a stem cell but not yet a neuron or other brain or nerve cell. Under the microscope, the researchers found that the patient-derived cells with the mutation grow much slower compared to the control group reprogrammed from a sibling without the disease.
This lethargic growth suggested that the cells had entered a zombie-like state called cellular senescence. Damage to DNA often causes cells to become senescent. When the research team looked at markers of genetic harm, they found three different indicators of injury to the genome, as well as an increased expression level of a cell cycle inhibitor gene associated with cellular senescence called CDKN2A.
Follow-up experiments showed that DNA damage was occurring during cell division, and it could be severe enough to cause cell death. Because the mutated gene had no known direct link to cell division, the investigators hypothesized that their observation might be due to interactions between multiple proteins. Their experiments compiled a list of 14 potential proteins that may be involved. Ten of them were connected to actin, one of the structural components that gives shape and structure to a cell.
During cell division, the actin filament needs to form an anchoring structure, and it usually forms a very round and even ring structure. But in the mutant cells, the altered actin forms a shrunken and irregularly shaped ring, so cells are not pulled apart in a symmetrical way and suffer damage. The scientists suspected that the mutation was affecting how the cell precisely coordinates the dynamic process of building this actin anchoring structure.
The research team demonstrated that mutant cells had altered actin dynamics, and that the cells could be treated with chemicals to stabilize the actin structure and improve the rate of normal cell division. The researchers already showed that if they correct some of the steps in the molecular processes, then they can fix some of the defects, at least in the cellular model.