分析数个患罕见高血压的病人的所有基因，耶鲁大学的研究人员发现了调节所有人血压的一种新机制。
由耶鲁大学科学家带领的国际研究小组所发现的研究结果，发表在一月二十二日的在线Nature杂志上，它可以帮助解释患高血压的十亿人出了什么故障。这项研究还证明了新DNA测序方法在寻找先前未知致病基因方面的威力。
研究小组使用一种称为全外显子测序的技术--所有基因组成的分析--来研究一种高血压的罕见遗传性形式，它以血中多余的钾含量为特点。在41个患病家庭的受影响成员中，他们发现引起此疾病的2个基因中任一个都有突变。
这2个基因在一个复合物中相互作用，此复合物靶向降解的其他蛋白质，他们协调着肾脏盐重吸收和钾分泌之间的平衡。
"这些基因以前没有被怀疑在调节血压中发挥作用，但如果他们被丧失，肾脏就不能阻止盐重吸收，从而导致高血压"， Richard Lifton说，他是斯特林教授和耶鲁大学遗传学系的主任，也是本文的通讯作者。
此突变以前很难找到，因为每个家庭中很少有人受影响，因此绘制基因位置的传统方法已无效。
"一个基因的突变几乎是所有新突变，它们发现于受影响的患者中，而不是他们的父母亲，而另一个基因的突变可能是显性或者是隐性。该外显子组测序技术是适合洞察这些复杂性"， 耶鲁大学的Lynn Boyden说，她也是本文的第一作者。
下一步就是建立这些新组成部分如何参与调节肾钠重吸收，希望找到干预高血压的新途径，而且高血压是一个主要的全球健康问题。
"我们正在寻找复杂机器的所有单个零件，我们需要了解他们是如何放在一起使机器工作的"， 霍华德休斯医学研究所的研究人员Lifton说。
来自10个国家的医生和在美国17个州招募的患这一罕见疾病的病人和家庭，参与此研究。
这项工作的资金来自HHMI和Leducq高血压大西洋网络、国立卫生研究院资助的奥布赖恩中心、国家研究资源中心授予的耶鲁大学临床和转化科学奖。（生物谷bioon.com）
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.
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