RESUMO
Increased susceptibility to gastric cancer has been associated with a wide range of host genetic and environmental factors, including Helicobacter pylori infection. Helicobacter pylori infection is postulated to initiate a progression through atrophic gastritis, metaplasia and dysplasia to cancer, and has been associated with reduction of acid output and dysregulation of stomach mucins. Here, we present the characterization of two mouse lines carrying mutant alleles of the gene encoding the Kcnq1 potassium channel, which very rapidly establish chronic gastritis in a pathogen-exposed environment. These mice develop gastric hyperplasia, hypochlorhydria and mucin dysregulation independent of infection. Metaplasia, dysplasia and pre-malignant adenomatous hyperplasia of the stomach have been observed in these Kcnq1 mutant mice, also independent of infection. The data presented here suggest that Kcnq1 mutant mice can be used both as an efficient model for the development of atrophic gastritis after infection and to determine the processes during the later stages of progression to gastric cancer independent of infection. Thus, Kcnq1 mutant mice are a powerful new tool for investigating the connection between acid balance, Helicobacter infection and mucin disruption in the progression to gastric cancer.
Assuntos
Adenoma/genética , Gastrite/genética , Canais de Potássio KCNQ/genética , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Acloridria/etiologia , Acloridria/genética , Acloridria/patologia , Adenoma/patologia , Alelos , Animais , Doença Crônica , Feminino , Mucinas Gástricas/metabolismo , Gastrite/etiologia , Gastrite/patologia , Predisposição Genética para Doença , Infecções por Helicobacter/complicações , Helicobacter pylori , Hiperplasia , Masculino , Metaplasia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Miocárdio/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Estria Vascular/patologia , Translocação GenéticaRESUMO
In the course of large-scale mutagenesis studies, we discovered a mutant that provides a new mouse model for human autosomal recessive polycystic kidney disease. Animals homozygous for this mutation, T(2;10)67Gso, present evidence of grossly cystic renal and hepatic tissue at birth and a limited survival time of 3-4 days. The recessively expressed phenotype is associated with inheritance of a reciprocal translocation involving mouse chromosomes 2 and 10. Here we describe the pathology and phenotype of this new mutation. The mapping of the chromosomal breakpoint to the 1.0-cM critical region defined for another mouse autosomal recessive polycystic kidney disease model, juvenile congenital polycystic kidney disease (jcpk), led us to undertake the complementation testing that confirmed T(2;10)67Gso and jcpk are allelic. Because of the strong resemblance between the phenotype associated with these mouse mutations and early childhood polycystic kidney disease, and because of advantages offered by reciprocal translocations for gene mapping and cloning, T(2;10)67Gso should prove a valuable asset for studies concerning this fatal disease.
