Mice with combined disruption of<i>Gpx1</i>and<i>Gpx2</i>genes have colitis

Esworthy, R. Steven; Aranda, Richard; Martı́n, Martı́n G.; Doroshow, James H.; Binder, Scott W.; Chu, Fong‐Fong

doi:10.1152/ajpgi.2001.281.3.g848

Cited by 268 publications

(187 citation statements)

References 32 publications

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“…Our findings suggest a specific and essential function for Yipf6 in granule secretion by Paneth and goblet cells of the intestinal tract, and a consequent role in the maintenance of intestinal homeostasis in mice. Because mouse mutations that cause DSS hypersensitivity have predicted intestinal inflammation in humans (1,5,(12)(13)(14)(15)(16)(17)(18) and particularly because the null allele of Yipf6 described here causes spontaneous disease, we suggest that YIPF6 should be regarded as a susceptibility locus when searching for causes of IBD in humans.…”

Section: Resultsmentioning

confidence: 92%

Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Brandl

Tomisato

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Using an environmentally sensitized genetic screen we identified mutations that cause inflammatory colitis in mice. The X-linked Klein-Zschocher (KLZ) mutation created a null allele of Yipf6, a member of a gene family believed to regulate vesicular transport in yeast, but without known functions in mammals. Yipf6 is a five transmembrane-spanning protein associated with Golgi compartments. Klein-Zschocher mutants were extremely sensitive to colitis induced by dextran sodium sulfate (DSS) and developed spontaneous ileitis and colitis after 16 mo of age in specific pathogen-free housing conditions. Electron microscopy, gene expression, and immunocytochemistry analyses provided evidence that impaired intestinal homeostasis stemmed from defective formation and secretion of large secretory granules from Paneth and goblet cells. These studies support a tissue-and organ-specific function for Yipf6 in the maintenance of intestinal homeostasis and implicate the orthologous human gene as a disease susceptibility locus.

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Section: Resultsmentioning

confidence: 92%

Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Brandl

Tomisato

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…GPX1, located in the more telomeric region, encodes the powerful antioxidant, glutathione peroxidase isoform 1. Double-knockout mice lacking both GPX1 and GPX2 activity were found to have an inflammatory bowel disease phenotype (30). RHOA, also in the telomeric region, encodes a small GTPase involved in blockage of stress fiber formation in the innate cellular immune response in the presence of effector proteins released by pathogenic Yersinia species (31).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci

Raelson

Little

Ruether

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

204

119

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Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.haplotype ͉ complex disease ͉ IL23R C rohn's disease (CD) is a chronic inflammatory bowel disease characterized by transmural inflammatory lesions that can affect the entire gastrointestinal tract (1). The lifetime prevalence is 0.5-1% in Caucasian populations (2) and reflects the combined effects of genetic predisposition and environmental factors (3). Genetic linkage and candidate gene approaches (4-14) have contributed to the elucidation of loci influencing genetic susceptibility to CD. More recently, genome-wide association (GWA) studies (15-21) have provided further insight into the molecular pathogenesis of the disease. The top candidate genes or loci that consistently replicate include NOD2, IL23R, ATG16L1, the IBD5 region on chromosome 5q31, and a region on 5p13.1 near the PTGER4 gene. The nature of these genes suggests that the major genetic risk factors for CD are involved in the innate immune response and destruction of intracellular bacteria.It is now clear that GWA studies provide a powerful and robust new tool for the identification of the multiple susceptibility alleles involved in complex diseases. Importantly, these types of studies have the ability to identify genes that impart only moderate increases in risk (21,22). However, most studies performed to date have identified only a few top signals, and the validation of true association among signals with lower statistical significance remains a challenge. In addition, most of the GWA studies to date have been performed by using general populations, for which very large sample sizes are required for success. They have also largely relied on single-marker analysis, with genome-wide haplotype-based association analyses receiving little attention.In early 2004, we conducted a GWA study for CD...

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“…Similarly, the gastrointestinal GPx-2 could be knocked out without impairing development. Even when crossbred with GPx-1 (Ϫ/Ϫ) mice, the resulting double knock-out mice were vital and only later developed an intestinal inflammatory syndrome (41). It is thus extremely unlikely that PHGPx, which is less abundant than any of its congeners, is of vital importance because of its antioxidant potential.…”

Section: Discussionmentioning

confidence: 99%

Distinct Promoters Determine Alternative Transcription of gpx-4 into Phospholipid-Hydroperoxide Glutathione Peroxidase Variants

Maiorino

Scapin

Ursini

et al. 2003

Journal of Biological Chemistry

117

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A nuclear variant of phospholipid-hydroperoxide glutathione peroxidase (PHGPx, GPx-4) was considered to be derived from alternative pre-mRNA splicing in testis and to regulate sperm maturation. The genomic sequence of rat gpx-4 was established and investigated in respect to expression into the cytosolic, mitochondrial, and nuclear forms of PHGPx. In silico analysis suggested the presence of two distinct promoter regions, the upstream one leading to transcripts translating into cPHGPx or mPHGPx and the downstream one yielding nPHGPx. The promoter activity of both regions was verified by luciferase-based reporter constructs in A7r5 and H9c2 cells. The data reveal that the formation of nPHGPx is due to alternative transcription and not to alternative splicing. Transcripts encoding nPHGPx were most abundant in testis although not restricted to this organ. This observation points to a general role of the nuclear PHGPx variant in regulating cell division.

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Mice with combined disruption ofGpx1andGpx2genes have colitis

Cited by 268 publications

References 32 publications

Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci

Distinct Promoters Determine Alternative Transcription of gpx-4 into Phospholipid-Hydroperoxide Glutathione Peroxidase Variants

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