Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
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DOI：
10.1038/ng.2716
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发表时间：
2013-09-01
期刊：
影响因子：
30.8
通讯作者：
Brown, Morris J.
中科院分区：
文献类型：
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作者：
Azizan, Elena A. B.;Poulsen, Hanne;Brown, Morris J.
至少5%的高血压患者患有肾上腺醛固酮腺瘤（APA）。据报告，APA中发生KCNJ 5的功能获得性突变和ATP 1A 1和ATP 2A 3的明显功能丧失性突变（1，2）。我们发现KCNJ 5突变常见于类似肾上腺皮质束状体皮质醇分泌细胞的APA，但在类似肾上腺皮质球状体醛固酮分泌细胞的APA亚群中不存在（3）。我们对10个肾小球样APA进行了外显子组测序，并确定了9个在编码Na+/K+ ATP酶α 1亚基的ATP 1A 1或编码Ca（v）1.3的CACNA 1D中具有体细胞突变。ATP 1A 1突变均在生理条件下引起内向漏电流，CACNA 1D突变诱导电压依赖性门控向更负的电压偏移，抑制失活或增加电流。许多具有这些突变的APA被
At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs(1,2). We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa(3). We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase alpha 1 subunit, or CACNA1D, encoding Ca(v)1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were