Two Princeton University studies are opening important new windows into understanding an untreatable group of common genetic disorders known as RASopathies that are characterized by distinct facial features, developmental delays, cognitive impairment and heart problems. The findings could help point the way toward personalized precision therapies for these conditions.

Although not widely known, RASopathies are among the most common genetic disorders, affecting approximately one child out of 1,000. RASopathies are caused by mutations within the RAS pathway, a biochemical system cells use to transmit information from their exterior to their interior.

Jindal and Goyal do their thesis research in the lab of Stanislav Shvartsman, professor of chemical and biological engineering and LSI. The researchers made the discoveries in zebrafish and fruit flies. Due to the evolutionary similarities in the RAS pathway across diverse species, changes in this pathway would also be similar.

The first paper presented a way to rank the severity of different mutations involved in RASopathies. The researchers introduced 16 mutations one at a time in developing zebrafish embryos. As each organism developed, clear differences in the embryos' shapes became evident, revealing the strength of each mutation. The same mutant proteins produced similarly varying degrees of defects in fruit flies. Some of the mutations the researchers tested were already known to be involved in human cancers. The researchers noted that these cancer–related mutations caused more severe deformations in the embryos, aligning with the medical community's ongoing efforts to adapt anti–cancer compounds to treat RASopathies.

The study suggested a path forward to human diagnostic advances, potentially enabling health care professionals to offer better diagnoses and inform caretakers about patients' disease progression.

The researchers demonstrated that the amount of medication necessary to correct the developmental defects in the zebrafish embryos corresponded with the mutation's severity – more severe mutations required higher dosages.

The more recent paper reports an unexpected twist in treatment approach to some RASopathies. Like all cellular pathways, the RAS pathway is a series of molecular interactions that changes a cell's condition. Conventional wisdom has held that RASopathies are triggered by overactive RAS pathways, which a biologist would call excessive signaling.

The study, however, found that some RASopathies could result from insufficient signaling along the RAS pathway in certain regions of the body. This means that drugs intended to treat RASopathies by tamping down RAS pathway signaling might actually make certain defects worse.

"To our knowledge, our study is the first to find lower signaling levels that correspond to a RASopathy disease," Goyal said. "Drugs under development are primarily RAS–pathway inhibitors aimed at reducing the higher activity, so maybe we need to design drugs that only target specific affected tissues, or investigate alternative, novel treatment options."

The study also found that RAS pathway mutations cause defects by changing the timing and specific locations of embryonic development.In the mutant cells the RAS pathway in certain parts of fly embryo abnormally activated before these cues were received. This early activation disturbed the delicate process of embryonic development. The researchers found similar behavior in zebrafish cells.

The paper, "In vivo severity ranking of Ras pathway mutations associated with developmental disorders," was published Jan. 3 in the Proceedings of the National Academy of Sciences journal. The paper, "Divergent effects of intrinsically active MEK variants on developmental Ras signaling," was published on Feb. 6 in the journal Nature Genetics.