NEW YORK (GenomeWeb) – Starting with exome sequence data for individuals with similar rare conditions, researchers from the Wellcome Sanger Institute, University of Exeter, and elsewhere have identified a recurrent gene alteration that appears to impact both pancreatic and brain development.
As they reported online today in the American Journal of Human Genetics, the analysis focused on more than 100 individuals with pancreatic malformation at birth, a condition known as pancreatic agenesis that is treated with hormone and pancreatic enzyme replacement therapy. In nine of these patients, the investigators did not see mutations in known pancreas development-related genes, prompting exome sequencing on these individuals as well as their unaffected parents, when available.
The search led to three individuals with the same de novo heterozygous missense mutation in the transcriptional repressor-coding gene CNOT1, along with similar pancreatic agenesis and abnormal brain development features, pointing to a previously unappreciated syndrome involving CNOT1. Based on follow-up experiments in mice, the team suggested that the newly-detected variant in CNOT1 likely stymies stem cell differentiation during development, prompting the pancreatic and brain development problems detected in the patients.
"This was the first time that anyone had realized that CNOT1 was important in pancreatic and neurological development, and has revealed a new genetic cause for pancreatic agenesis," co-first author Elisa De Franco, a biomedical and clinical science researcher at the University of Exeter Medical School, said in a statement.
The CNOT1 alteration identified in the three pancreatic agenesis cases is known as p.Arg535Cys — a missense change that arose de novo in at least two of the three individuals. In the third case, researchers noted that the patient's father did not have the CNOT variant, though maternal exome data was not available to determine unequivocally that it was a new genetic change.
"This is the [fifth] gene causative of pancreatic agenesis described so far and the first pancreatic agenesis gene that is thought to be important for maintaining stem cells' pluripotency," the authors explained, adding that results from their analyses "suggest a new mechanism by which impairment of the very early stages of development result in pancreatic agenesis and abnormal brain development."
The team noted that its experiments on mice carrying the mouse version of that CNOT1 mutation showed altered pancreatic and neurological development, including diminutive upper pancreas portions, gene expression shifts in pancreatic tissue, brain changes, eye defects, and other morphological changes.
The phenotypes in the mutant mice and mouse embryos lined up with clinical features found in the patients, the authors noted, "confirming that the de novo CNOT1 mutation is indeed the cause of their disease."