RT Journal Article SR Electronic T1 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 JF Disease Models & Mechanisms JO Dis Models Mech FD The Company of Biologists Limited SP 975 OP 984 DO 10.1242/dmm.025890 VO 9 IS 9 A1 Calvete, Oriol A1 Varro, Andrea A1 Pritchard, D. Mark A1 Barroso, Alicia A1 Oteo, Marta A1 Morcillo, Miguel Ángel A1 Vargiu, Pierfrancesco A1 Dodd, Steven A1 Garcia, Miriam A1 Reyes, José A1 Ortega, Sagrario A1 Benitez, Javier YR 2016 UL http://dmm.biologists.org/content/9/9/975.abstract AB By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4aR703C mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.