RESUMO
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
Assuntos
Diarreia/genética , Doenças Inflamatórias Intestinais/genética , Receptores de Enterotoxina/genética , Adulto , Idoso , Estudos de Casos e Controles , Diarreia/metabolismo , Regulação para Baixo , Saúde da Família , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íleo/patologia , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Proteína Adaptadora de Sinalização NOD2/genética , Noruega , Plasma/química , Medição de Risco , Síndrome , Adulto JovemRESUMO
Several transcription regulators play key roles during pituitary morphogenesis. Well known intrinsic signals of the adenohypophysis such as the K(50)paired-like homeodomain proteins regulate commitment, proliferation, differential specification and maintenance of adenohypophyseal cells. We have cloned and successively characterized the mRNA localization of three pitx gene-pairs and three of their splice variants in salmon, pitx1alpha, pitx1beta; pitx2alpha, pitx2beta; pitx3alpha, pitx3beta; pitx1alphash, pitx1betash and pitx2alphaA. The high level of conservation between the pitx paralog-pairs indicates that they likely arose from lineage-specific genome duplication. We also report the isolation of a pitx1 gene in zebrafish. Comparative ISH studies of zebrafish, salmon and mouse pitx genes indicate both conservation and divergence of spatial expression domains in vertebrates. Significant differences were observed between the expressions of pitx orthologs during pituitary development. We suggest that the ancestral pituitary expression at early and late events of morphogenesis is preserved in different species through complementary shuffling of expression between the distinct pitx members of the family. Moreover, ISH analysis of the pitx salmon repertoire shows rapid evolution in this lineage, differences in spatio-temporal expression are observed between gene duplicates.
