In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in NOS1AP, encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of NOS1AP/Nos1ap and neighboring C1orf226/Gm7694, which precludes NOS1 binding, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694-/- mice, whose allele exclusively disrupts the intergenic product, developed NS phenotypes. In two human NS subjects, we identified causative NOS1AP splice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generated a faithful mouse model of NOS1AP-associated NS, which responded to anti-proteinuric treatment. This study highlights the importance of intergenic splicing and a potential treatment avenue in a mendelian disorder.

中文翻译：

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基因间 NOS1AP-C1orf226 位点的隐性变异导致对抗蛋白尿治疗有反应的单基因肾病

在遗传疾病中，疾病基因的准确表达景观和忠实的动物模型将分别实现精确的基因诊断和治疗发现。我们之前发现，编码一氧化氮合酶 1 (NOS1) 衔接蛋白的 NOS1AP 变异会导致单基因肾病综合征 (NS)。在这里，我们确定 NOS1AP/Nos1ap 和邻近的 C1orf226/Gm7694 的基因间剪接产物（阻止 NOS1 结合）是哺乳动物肾脏转录和蛋白质组数据中的主要亚型。 Gm7694-/- 小鼠的等位基因专门破坏基因间产物，从而形成 NS 表型。在两名人类 NS 受试者中，我们鉴定了致病性 NOS1AP 剪接变体，其中包括一种预计会消除基因间剪接但最初根据规范转录本被错误分类为良性的变体。最后，通过修改遗传背景，我们生成了一个忠实的 NOS1AP 相关 NS 小鼠模型，该模型对抗蛋白尿治疗有反应。这项研究强调了基因间剪接的重要性以及孟德尔疾病的潜在治疗途径。