Saturation Screening of the Druggable Mammalian Genome

BeltrandelRio, Hector; Kern, Florian; Lanthorn, Thomas H.; Oravecz, Tamás; Piggott, James; Powell, David R.; Ramírez‐Solís, Ramiro; Sands, Arthur; Zambrowicz, Brian

doi:10.1002/0470014067.ch10

Cited by 28 publications

(38 citation statements)

References 49 publications

(54 reference statements)

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“…Wnk1 heterozygotes displayed a reduction in blood pressure of Ϸ12 mmHg (1 mmHg ϭ 133 Pa) (Fig. 5) and no notable phenotype in all other areas examined (9,24). This decrease in blood pressure was not related to any pathological changes in the kidney, because no notable differences in kidney histology were observed (data not shown).…”

Section: Fig 1 Simultaneous Gene Mutation and Identification By Genmentioning

confidence: 85%

“…Mice heterozygous for the Wnk1 gene-trap mutation were subjected to our standard phenotypic analysis protocol, which is applied to all lines generated and includes tests of behavior, immunology͞inflammation, obesity͞diabetes, bone, cell proliferation, and cardiovascular function (described in detail in ref. 24). Wnk1 heterozygotes displayed a reduction in blood pressure of Ϸ12 mmHg (1 mmHg ϭ 133 Pa) (Fig.…”

Section: Fig 1 Simultaneous Gene Mutation and Identification By Genmentioning

confidence: 99%

See 1 more Smart Citation

Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention

Zambrowicz

Abuin

Ramirez-Solis

et al. 2003

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

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The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in ≈60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach

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Section: Fig 1 Simultaneous Gene Mutation and Identification By Genmentioning

confidence: 85%

Section: Fig 1 Simultaneous Gene Mutation and Identification By Genmentioning

confidence: 99%

Wnk1 kinase deficiency lowers blood pressure in mice: A gene-trap screen to identify potential targets for therapeutic intervention

Zambrowicz

Abuin

Ramirez-Solis

et al. 2003

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

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305

329

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“…Briefly, wt and hom mice were subjected to a comprehensive battery of phenotype screening exams as previously described. 1,34 Screening assays included behavioral tests (such as circadian rhythm, open field, functional observation battery based on a subset of behavioral tests derived from the Irwin screen, 7 inverted screen, hot plate, prepulse inhibition of the acoustic startle response, tail suspension, marble burying, formalin paw assay, and context trace conditioning), fundoscopy and retinal angiography exams, blood pressure and heart rate measurements, serum chemistries, insulin levels, glucose tolerance testing, hematology, peripheral blood fluorescence activated cell sorting analysis, urinalysis, dual-energy x-ray absorptiometry scans, computed tomography scans, microcomputed tomography scans, fertility testing, skin fibroblast proliferation assays, and pathology.…”

Section: Phenotypic Testingmentioning

confidence: 99%

Histopathological and Neurological Features of Atg4b Knockout Mice

et al. 2010

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This investigation found that genetic inactivation of mouse Atg4b, 1 of the 4 mammalian homologs of the autophagy-related gene Atg4, resulted in amorphous globular bodies in the neuropil of the deep cerebellar nuclei and adjacent vestibular nuclei but nowhere else in the brain or other tissues. The spheroid-like bodies in the deep cerebellar and vestibular nuclei showed heterogeneous composition, reactivity with anti-ubiquitin antibody, and staining characteristics of proteinaceous material. Atg4b-deficient (Atg4b -/-) mice also showed a mild but measurable impairment of motor performance on the Rotarod. Atg4b-/-mice produced by breeding heterozygous parents were produced at a slightly lower than expected ratio to heterozygous and wild-type siblings but showed no other clear abnormalities in a battery of screening tests. These findings appear to be different than those reported for inactivation of other Atg4 homologs, suggesting that these homologs have tissue-specific functions beyond redundancy.

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“…Likewise, comprehensive clinical diagnostic and pathologic analysis (described in detail in Ref. 25), including tests of inflammation, behavior, obesity, diabetes, bone, cell proliferation, and cardiovascular function, did not demonstrate significant differences in Sh2d3c 2/2 mice relative to their WT littermates (data not shown).…”

Section: Statistical Analysesmentioning

confidence: 79%