A knockin mouse model for human ATP4aR703C mutation identified in familial gastric neuroendocrine tumors recapitulates the premalignant condition of the human disease and suggests new therapeutic strategies.

摘要: By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes proton pump responsible for gastric acidification. This causes an aggressive familial type I neuroendocrine tumor homozygous individuals. Affected individuals show early onset of disease, characterized by hypoacidity, hypergastrinemia, iron-deficiency anemia, intestinal metaplasia and, one case, associated adenocarcinoma. Total gastrectomy was performed as definitive treatment all affected We now describe generation and characterization knockin mouse model ATP4a(R703C) to better understand tumorigenesis process. Homozygous mice recapitulated most phenotypical alterations that were observed individuals, strongly suggesting this is primary alteration disease development. developed premalignant condition with severe hyperplasia, dysplasia glandular stomach. Interestingly, acidification mice, induced 3% HCl acid drinking water, prevented (if treated from birth) or partially reverted during adulthood) development stomach rescued abnormal biochemical parameters. therefore suggest that, model, achlorhydria contributes greater extent than hypergastrinemia. Furthermore, our represents unique novel tool studying pathologies disturbances secretion.