Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.

We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase).

In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro.

Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

在过去的十年中，遗传技术的进步导致了罕见的肾镁和盐处理遗传性疾病的鉴定。然而，大约 20% 的肾小管病患者缺乏基因诊断。

我们对患有新型遗传性失盐性肾小管病的患者队列进行了全外显子组和基因组测序；低镁血症; 和扩张型心肌病。我们还对已识别的RRAGD变体进行了后续的体外功能分析，RRAGD 是一种编码小型 Rag 鸟苷三磷酸酶 (GTPase) 的基因。

在来自不相关家庭的 8 名患有以低镁血症、低钾血症、盐消耗和肾钙质沉着症为特征的肾小管病的儿童中，我们发现了RRAGD中的杂合错义变异，这些变异大多是从头发生的。这些患者中有 6 名还患有扩张型心肌病，3 名接受了心脏移植。我们在RRAGD中发现了一个杂合变体，该变体与具有相似肾脏表现的大家族的八个成员的表型分离。GTPase RagD，由RRAGD编码, 在介导氨基酸信号转导至雷帕霉素复合物 1 (mTORC1) 的机制靶点中发挥作用。沿哺乳动物肾单位的 RagD 表达包括粗升肢和远曲小管。已鉴定的RRAGD变体显示可在体外诱导 mTOR 信号传导的组成型激活。

我们的研究结果确立了一种新的疾病，我们称之为常染色体显性遗传性肾低镁血症 (ADKH-RRAGD)，它结合了电解质丢失性肾小管病和扩张型心肌病。这种情况是由RRAGD基因的变异引起的，该基因编码 Rag GTPase D；这些变体导致 mTOR 信号的激活，表明 Rag GTPase D 对肾电解质处理和心脏功能的关键作用。