BACKGROUND Primary aldosteronism (PA) is a common cause of human hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 are found in at least 80% of aldosterone-producing adenomas, which cause unilateral PA in humans. Somatic mutations have been identified infrequently in 7 other genes; few of these were known to play a role in aldosterone secretion before the discovery of their mutations. Interrogating somatic mutations in the domestic cat, in which spontaneous PA is also known to occur, might improve the understanding of normal adrenal gland physiology and the pathophysiology of PA. METHODS DNA and RNA extracted from tissue from 13 cats with unilateral aldosterone-secreting tumors, including 8 carcinomas and 5 adenomas, underwent whole genome sequencing, targeted Sanger sequencing, and RNA sequencing. Single-nucleotide substitution variants were filtered to select those with a predicted deleterious effect on protein function and a suspected role in aldosterone secretion. RESULTS Probable functional somatic single-nucleotide polymorphisms (n=8) were found in 3 adenomas and 2 carcinomas. Mutations with predicted significant effects were identified in 2 genes also mutated in human PA; GNAQ and CTNNB1, and in a residue of CACNA1C analogous to a common CACNA1D mutation. In contrast to humans, CACNA1C expression was much greater than CACNA1D in both feline tumor and nontumor adrenal tissue. No mutations were identified in KCNJ5, CACNA1D, ATP1A1, or ATP2B3. CONCLUSIONS Similar mutations were identified in cats to those found in humans. It is, therefore, likely that both species have shared underlying selection pressures for mutations that increase aldosterone secretion.

中文翻译：

---

猫醛固酮分泌肿瘤的体细胞 GNAQ、CTNNB1 和 CACNA1C 突变。


背景 原发性醛固酮增多症 （PA） 是人类高血压的常见原因。KCNJ5、CACNA1D、ATP1A1 和 ATP2B3 的体细胞突变存在于至少 80% 的醛固酮分泌腺瘤中，这会导致人类单侧 PA。在其他 7 个基因中很少发现体细胞突变;在发现它们的突变之前，已知其中很少有在醛固酮分泌中发挥作用。询问家猫的体细胞突变，其中也已知发生自发性 PA，可能会提高对正常肾上腺生理学和 PA 病理生理学的理解。方法 对 13 只单侧醛固酮分泌肿瘤（包括 8 只癌和 5 只腺瘤）猫的组织中提取的 DNA 和 RNA 进行全基因组测序、靶向 Sanger 测序和 RNA 测序。过滤单核苷酸取代变体，以选择那些对蛋白质功能具有预测有害影响且怀疑在醛固酮分泌中起作用的变体。结果 在 3 例腺瘤和 2 例癌中发现可能的功能性体细胞单核苷酸多态性 （n=8）。在人类 PA 中也发生突变的 2 个基因中发现了具有预测显着影响的突变;GNAQ 和 CTNNB1 以及 CACNA1C 的残基类似于常见的 CACNA1D 突变。与人类相比，CACNA1C在猫科动物和非肿瘤肾上腺组织中的表达远大于 CACNA1D。在 KCNJ5 、 CACNA1D 、 ATP1A1 或 ATP2B3 中未发现突变。结论 在猫中发现的突变与在人类中发现的突变相似。因此，两个物种很可能对增加醛固酮分泌的突变具有共同的潜在选择压力。