Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome).
Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome).
复制标题
DOI：
10.1042/cs20130326
复制
发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
O'Shaughnessy KM
中科院分区：
文献类型：
--
作者：
Glover M;Ware JS;Henry A;Wolley M;Walsh R;Wain LV;Xu S;Van't Hoff WG;Tobin MD;Hall IP;Cook S;Gordon RD;Stowasser M;O'Shaughnessy KM
对具有罕见遗传形式的低血压和高血压的家族的研究是探索血压控制的分子病理生理学的最成功的策略之一，并且揭示了远端肾单位Na+重吸收的失调是一种常见的机制。FHHt（家族性高钾血症性高血压;也称为戈登综合征）是一种盐依赖型高血压，由噻嗪敏感性Na+-Cl−协同转运蛋白NCC [也称为SLC 12 A3（溶质载体家族12成员3）]的调节因子突变引起，可通过噻嗪类利尿剂和/或饮食盐限制有效治疗。至少有四个基因的变异可以引起FHHt，包括WNK 1 [无赖氨酸（=K）1]和WNK 4，KLHL 3（kelch样家族成员3）和CUL 3（cullin 3）。在本研究中，我们已经确定了新的致病变异CUL 3和KLHL 3分离在63%的家系与以前无法解释的FHHt，证实了这些最近描述的FHHt基因的重要性。我们已经在两个不相关的受影响个体中得出结论，CUL 3中罕见的内含子变异导致外显子9的跳跃，如先前所提出的。KLHL 3变异体都发生在kelch重复结构域中，因此可能破坏WNK复合物结合。我们在该人群中没有发现SLC 4A 8（一种替代的噻嗪敏感性钠转运蛋白）中存在任何合理的致病变异的证据。本研究的结果支持现有的证据表明，CUL 3和KLHL 3基因产物是生理上重要的调节剂噻嗪敏感的远端肾单位NaCl重吸收，因此潜在的有趣的新的抗高血压药物的目标。由于我们的非WNK FHHt家族中有三分之一没有合理的CUL 3或KLHL 3变体，因此可能还有其他尚未发现的噻嗪敏感途径调节因子。本研究发现了戈登综合征患者的CUL 3和KLHL 3基因的新突变。CUL 3突变显示导致外显子9剪接缺陷。三分之一的戈登综合征家庭仍然没有基因诊断。
The study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+–Cl− co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes can cause FHHt, including WNK1 [With No lysine (=K) 1] and WNK4, KLHL3 (kelch-like family member 3), and CUL3 (cullin 3). In the present study we have identified novel disease-causing variants in CUL3 and KLHL3 segregating in 63% of the pedigrees with previously unexplained FHHt, confirming the importance of these recently described FHHt genes. We have demonstrated conclusively, in two unrelated affected individuals, that rare intronic variants in CUL3 cause the skipping of exon 9 as has been proposed previously. KLHL3 variants all occur in kelch-repeat domains and so probably disrupt WNK complex binding. We have found no evidence of any plausible disease-causing variants within SLC4A8 (an alternative thiazide-sensitive sodium transporter) in this population. The results of the present study support the existing evidence that the CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron NaCl reabsorption, and hence potentially interesting novel anti-hypertensive drug targets. As a third of our non-WNK FHHt families do not have plausible CUL3 or KLHL3 variants, there are probably additional, as yet undiscovered, regulators of the thiazide-sensitive pathways. The present study has found new mutations in the CUL3 and KLHL3 genes of patients with Gordon's syndrome. CUL3 mutations were shown to cause a defect in the splicing of exon 9. One-third of families with Gordon's syndrome remain without a genetic diagnosis.