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Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities 总被引:2,自引:0,他引:2
Boyden LM Choi M Choate KA Nelson-Williams CJ Farhi A Toka HR Tikhonova IR Bjornson R Mane SM Colussi G Lebel M Gordon RD Semmekrot BA Poujol A Välimäki MJ De Ferrari ME Sanjad SA Gutkin M Karet FE Tucci JR Stockigt JR Keppler-Noreuil KM Porter CC Anand SK Whiteford ML Davis ID Dewar SB Bettinelli A Fadrowski JJ Belsha CW Hunley TE Nelson RD Trachtman H Cole TR Pinsk M Bockenhauer D Shenoy M Vaidyanathan P Foreman JW Rasoulpour M Thameem F Al-Shahrouri HZ Radhakrishnan J Gharavi AG Goilav B 《Nature》2012,482(7383):98-102
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. 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. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin 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. 相似文献
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A briefing workshop was run in an effort to involve its participants in choosing a strategic direction, and eventual form, for a proposed facility. The workshop was an action research, participative process that sought to improve final design by preconsultation with some relevant stakeholders. This paper will specifically focus on our attempt to use strategic planning software at an early stage of such a workshop. It discusses and illustrates the difficulties of importing a new technique into an established, professional setting where activities and roles may be expressed, or assumed, on the basis of previous experience. More exactly, although we hoped to use our software to analyze and explore participants' design styles, and so predict their likely choice of design option, the architects present undermined such analyzes by playing a role rather than telling the software what they really thought about the various strategic choices. Hence it was, in some ways, a waste of time using our software. We speculate below whether such undermining might be symptomatic of deep philosophical differences between the workshop organizers, planners, and architects. We also examine whether such differences bode ill for the future of architecture. 相似文献
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Woodgett J 《Nature》2008,454(7207):939
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