Monticone Silvia, Bandulik Sascha, Stindl Julia, Zilbermint Mihail, Dedov Ivan, Mulatero Paolo, Allgaeuer Michael, Lee Chyi-Chia Richard, Stratakis Constantine A, Williams Tracy A, Tiulpakov Anatoly
Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences (S.M., P.M., T.A.W.), University of Torino, Torino 10124 Italy; Medical Cell Biology (S.B., J.S.), University of Regensburg, 93053 Regensburg, Germany; Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (M.Z., C.A.S.), and Laboratory of Pathology (M.A., C.-C.R.L.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892; and Department of Inherited Endocrine Disorders (I.D., A.T.), Endocrinology Research Centre, Moscow 117036, Russia.
J Clin Endocrinol Metab. 2015 Jan;100(1):E114-8. doi: 10.1210/jc.2014-3636.
Familial hyperaldosteronism type III (FH-III) is a rare and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K(+) channel 4 (Kir3.4), underlie the molecular basis of FH-III.
The objective of the study was to investigate the effects of a de novo germline KCNJ5 mutation.
We describe the case of a girl who came to medical attention at the age of 2 years because of polydipsia, polyuria, and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. Genomic DNA was isolated and KCNJ5 sequenced. Human adrenocortical cells were used as an in vitro model for the functional characterization of the mutant channel.
KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na(+)-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil.
Herein we report the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.
III型家族性醛固酮增多症（FH-III）是一种罕见的临床异质性疾病，可表现出轻度和重度表型。KCNJ5基因中的点突变影响内向整流钾通道4（Kir3.4）的离子选择性，是FH-III的分子基础。
本研究的目的是调查一种新生的种系KCNJ5突变的影响。
我们描述了一名2岁女孩的病例，她因烦渴、多尿和发育不良前来就医。该患者患有高血压和低钾血症，根据极高的醛固酮水平和受抑制的血浆肾素活性被诊断为原发性醛固酮增多症。分离基因组DNA并对KCNJ5进行测序。使用人肾上腺皮质细胞作为突变通道功能表征的体外模型。
对索引病例及其父母的KCNJ5测序揭示了一种新生的p.Glu145Gln种系突变。该替代导致肾上腺细胞的钠依赖性去极化并增加细胞内钙浓度，从而激活NR4A2的转录，进而激活CYP11B2的转录。药理学研究表明，突变通道对替他品-Q和钙通道阻滞剂维拉帕米不敏感。
在此我们报告鉴定出一种新的KCNJ5种系突变，该突变导致严重的醛固酮增多症，在婴儿期表现为尿崩症症状。本研究结果进一步阐明了FH-III的病因，并扩展了我们对这种罕见疾病的认识。
