6 research outputs found
Cultural Mythologies of Russian Modernism: From the Golden Age to the Silver Age. California Slavic Studies, vol. 15. Eds. Boris Gasparov, Robert P. Hughes and Irina Paperno. Berkeley: University of California Press, 1992. 494 pp. Index. $50.00, hard bound.
Socialist Realism: The Impossible Aesthetic. By RĂ©gine Robin. Trans. Catherine Porter. Stanford: Stanford University Press, 1992. 345 pages. Name index. $45.00, hard bound.
Beyond Metafiction: Self-Consciousness in Soviet Literature. By David Shepherd . New York: Oxford University Press, 1992. 260 pp. Index. $59.00, hard bound.
Epigenetic Mechanisms of Promigratory Chemokine CXCL14 Regulation in Human Prostate Cancer Cells
Crake’s aesthetic: Genetically modified humans as a form of art in Margaret Atwood’s Oryx and Crake
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion(1). Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains(2-8). Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate(9) and cullin(5) binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis