Overview of the genetic determinants of primary aldosteronism.
Overview of the genetic determinants of primary aldosteronism.
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DOI：
10.2147/tacg.s45620
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Desailloud R
中科院分区：
文献类型：
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作者：
Al-Salameh A;Cohen R;Desailloud R
原发性醛固酮增多症是继发性高血压最常见的原因。该综合征占所有高血压病例的10%，主要由双侧肾上腺增生或产生醛固酮的腺瘤引起。在过去的几年里，外显子组测序的使用极大地提高了我们对这种综合征的理解。KCNJ5、ATP1A1、ATP2B3或CACNA1D基因在半数以上的醛固酮腺瘤中存在体细胞突变(分别为~40%、~6%、~1%和~8%)。现在已知KCNJ5的种系功能获得突变会导致家族性III型醛固酮增多症，另一种形式的遗传性醛固酮增多症已被报道存在CACNA1D种系突变的患者。这些基因编码了控制肾小球带细胞质膜上离子动态平衡的通道。此外，所有这些突变都调节着相同的途径，在这种途径中，细胞内钙水平的升高会导致醛固酮的过度产生和(在某些情况下)肾上腺细胞的增殖。从临床的角度来看，这些突变的发现对患者管理具有潜在的影响。突变的通道可能是药物的靶点，以控制与激素和过度生长相关的表现。此外，这些突变中的一些与高细胞周转率有关，并可能通过对无细胞(循环)DNA的测序进行诊断。然而，携带这些突变的患者的基因-表型相关性尚未确定。尽管最近取得了这些进展，但仍有许多工作要做，以阐明散发性双侧肾上腺增生的未知机制。
Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia.