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

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Resumen:

 By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4agene, 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.

Autores/as (por orden de autoría): : Calvete O, Varro A, Pritchard DM, Barroso A, Oteo M, Morcillo MÁ, Vargiu P, Dodd S, Garcia M, Reyes J, Ortega S, Benitez J.

Título: 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

Clave: A

Revista: Disease models & mechanisms

Volumen: 9

Página inicial:   975   Página final: 984

Fecha: Sep 2016

Publicación indexada en JCR: Sí

Base de datos de indexación:  JCR Any / Año: 2016

Índice de impacto: 4.691

Posición relativa que ocupa la revista en la categoría: Q1

Categoría: GASTROENTEROLOGY & HEPATOLOGY

Número de citaciones en JCR: 1

Número de citaciones total: 1

Otros indicios de calidad: 

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