Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
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DOI：
10.1038/nature10814
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发表时间：
2012-01-22
期刊：
影响因子：
64.8
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Boyden, Lynn M.;Choi, Murim;Choate, Keith A.;Nelson-Williams, Carol J.;Farhi, Anita;Toka, Hakan R.;Tikhonova, Irina R.;Bjornson, Robert;Mane, Shrikant M.;Colussi, Giacomo;Lebel, Marcel;Gordon, Richard D.;Semmekrot, Ben A.;Poujol, Alain;Valimaki, Matti J.;De Ferrari, Maria E.;Sanjad, Sami A.;Gutkin, Michael;Karet, Fiona E.;Tucci, Joseph R.;Stockigt, Jim R.;Keppler-Noreuil, Kim M.;Porter, Craig C.;Anand, Sudhir K.;Whiteford, Margo L.;Davis, Ira D.;Dewar, Stephanie B.;Bettinelli, Alberto;Fadrowski, Jeffrey J.;Belsha, Craig W.;Hunley, Tracy E.;Nelson, Raoul D.;Trachtman, Howard;Cole, Trevor R. P.;Pinsk, Maury;Bockenhauer, Detlef;Shenoy, Mohan;Vaidyanathan, Priya;Foreman, John W.;Rasoulpour, Majid;Thameem, Farook;Al-Shahrouri, Hania Z.;Radhakrishnan, Jai;Gharavi, Ali G.;Goilav, Beatrice;Lifton, Richard P.
高血压影响着10亿人，是心血管疾病的主要可逆危险因素。一种罕见的孟德尔综合征，假性醛固酮减少症II型（PHAII），以高血压、高钾血症和代谢性酸中毒为特征，揭示了以前未被认识的生理调节肾盐重吸收与K+和H+排泄之间的平衡。我们利用外显子组测序鉴定了41种PHAII的Kelch-like 3 （KLHL3）或Cullin 3 （CUL3）突变。KLHL3突变要么是隐性的，要么是显性的，而CUL3突变是显性的，主要是新生的。CUL3和BTB-Kelch蛋白（如KLHL3）是Cullin/RING E3连接酶复合物（CRLs）的组分，该复合物泛素化与Kelch螺旋桨结构域结合的底物。显性KLHL3突变分别聚集在Kelch螺旋桨结构域和BTB结构域的短片段中，这些结构域与底物和Cullin结合有关。不同的CUL3突变都导致外显子9的跳跃，产生帧内缺失。因为显性KLHL3和CUL3突变都是表型隐性KLHL3功能缺失突变，它们可能会消除KLHL3底物的泛素化。噻嗪类利尿剂可逆转疾病特征，噻嗪类利尿剂可抑制肾远端肾元中的Na-Cl共转运蛋白（NCC）；KLHL3和CUL3在该位置表达，提示KLHL3/CUL3突变、Na-Cl重吸收增加和疾病发病机制之间存在机制联系。这些发现证明了外显子组测序在疾病基因鉴定中的实用性，尽管存在位点异质性、混合传播模型和频繁的新生突变的复杂性，并确立了KLHL3/CUL3在血压、K+和pH稳态中的基本作用。
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion. We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) 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 (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.
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影响因子：
30.8
作者：
Lalioti, Maria D.;Zhang, Junhui;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
影响因子：
64.8
作者：
FUSHIMI, K;UCHIDA, S;SASAKI, S
通讯作者：
SASAKI, S
DOI：
10.1152/ajprenal.00441.2009
发表时间：
2010-08-01
影响因子：
4.2
作者：
Ko, Benjamin;Kamsteeg, Erik-Jan;Hoover, Robert S.
通讯作者：
Hoover, Robert S.
影响因子：
12.3
作者：
Stogios, Peter J;Downs, Gregory S;Jauhal, Jimmy J S;Nandra, Sukhjeen K;Prive, Gilbert G
通讯作者：
Prive, Gilbert G
影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR