分析數(shù)個(gè)患罕見高血壓的病人的所有基因,，耶魯大學(xué)的研究人員發(fā)現(xiàn)了調(diào)節(jié)所有人血壓的一種新機(jī)制,。
由耶魯大學(xué)科學(xué)家?guī)ьI(lǐng)的國(guó)際研究小組所發(fā)現(xiàn)的研究結(jié)果,，發(fā)表在一月二十二日的在線Nature雜志上,，它可以幫助解釋患高血壓的十億人出了什么故障。這項(xiàng)研究還證明了新DNA測(cè)序方法在尋找先前未知致病基因方面的威力,。
研究小組使用一種稱為全外顯子測(cè)序的技術(shù)--所有基因組成的分析--來研究一種高血壓的罕見遺傳性形式,，它以血中多余的鉀含量為特點(diǎn)。在41個(gè)患病家庭的受影響成員中,，他們發(fā)現(xiàn)引起此疾病的2個(gè)基因中任一個(gè)都有突變,。
這2個(gè)基因在一個(gè)復(fù)合物中相互作用,，此復(fù)合物靶向降解的其他蛋白質(zhì)，他們協(xié)調(diào)著腎臟鹽重吸收和鉀分泌之間的平衡,。
"這些基因以前沒有被懷疑在調(diào)節(jié)血壓中發(fā)揮作用,，但如果他們被喪失，腎臟就不能阻止鹽重吸收,，從而導(dǎo)致高血壓",， Richard Lifton說，他是斯特林教授和耶魯大學(xué)遺傳學(xué)系的主任,，也是本文的通訊作者,。
此突變以前很難找到，因?yàn)槊總€(gè)家庭中很少有人受影響,，因此繪制基因位置的傳統(tǒng)方法已無效,。
"一個(gè)基因的突變幾乎是所有新突變，它們發(fā)現(xiàn)于受影響的患者中,，而不是他們的父母親，而另一個(gè)基因的突變可能是顯性或者是隱性,。該外顯子組測(cè)序技術(shù)是適合洞察這些復(fù)雜性",， 耶魯大學(xué)的Lynn Boyden說，她也是本文的第一作者,。
下一步就是建立這些新組成部分如何參與調(diào)節(jié)腎鈉重吸收,，希望找到干預(yù)高血壓的新途徑，而且高血壓是一個(gè)主要的全球健康問題,。
"我們正在尋找復(fù)雜機(jī)器的所有單個(gè)零件,，我們需要了解他們是如何放在一起使機(jī)器工作的"， 霍華德休斯醫(yī)學(xué)研究所的研究人員Lifton說,。
來自10個(gè)國(guó)家的醫(yī)生和在美國(guó)17個(gè)州招募的患這一罕見疾病的病人和家庭,，參與此研究。
這項(xiàng)工作的資金來自HHMI和Leducq高血壓大西洋網(wǎng)絡(luò),、國(guó)立衛(wèi)生研究院資助的奧布賴恩中心,、國(guó)家研究資源中心授予的耶魯大學(xué)臨床和轉(zhuǎn)化科學(xué)獎(jiǎng)。（生物谷bioon.com）
doi:10.1038/nature10814
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Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Lynn M. Boyden, Murim Choi, Keith A. Choate, Carol J. Nelson-Williams, Anita Farhi, Hakan R. Toka, Irina R. Tikhonova, Robert Bjornson, Shrikant M. Mane, Giacomo Colussi, Marcel Lebel, Richard D. Gordon, Ben A. Semmekrot, Alain Poujol, Matti J. V?lim?ki, Maria E. De Ferrari, Sami A. Sanjad, Michael Gutkin, Fiona E. Karet, Joseph R. Tucci, Jim R. Stockigt, Kim M. Keppler-Noreuil, Craig C. Porter, Sudhir K. Anand, Margo L. Whiteford, Ira D. Davis, Stephanie B. Dewar, Alberto Bettinelli, Jeffrey J. Fadrowski, Craig W. Belsha, Tracy E. Hunley, Raoul D. Nelson, Howard Trachtman, Trevor R. P. Cole, Maury Pinsk, Detlef Bockenhauer, Mohan Shenoy, Priya Vaidyanathan, John W. Foreman, Majid Rasoulpour, Farook Thameem, Hania Z. Al-Shahrouri, Jai Radhakrishnan, Ali G. Gharavi, Beatrice Goilav, Richard P. Lifton
Abstract 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+ excretion1. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3mutations 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 domains2, 3, 4, 5, 6, 7, 8. Dominant KLHL3mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate9 and cullin5 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 CUL3mutations, 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.
