Departments of Internal Medicine (Nephrology) and.
Departments of Nephrology.
J Am Soc Nephrol. 2019 Nov;30(11):2091-2102. doi: 10.1681/ASN.2019030298. Epub 2019 Aug 8.
Mutations in or cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the gene product, the membrane protein polycystin-1 (PC1).
We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, , and cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups.
Two patients in the clinically defined cohort had rare loss-of-function variants in , which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. assays showed that inactivation of results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without mutations.
is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.
或中的突变导致典型的常染色体显性多囊肾病（ADPKD），这是最常见的单基因肾脏疾病。ADPKD 谱中显性遗传多囊肾和肝疾病也由至少其他六个基因的突变引起，这些基因对于内质网中蛋白质生物发生是必需的，其丧失导致膜蛋白多囊蛋白-1（PC1）的基因产物的产生缺陷。
我们使用全外显子组测序在 122 名具有遗传上未解决的 ADPKD 或多囊肝病临床诊断的患者队列中鉴定候选基因，以及基于细胞的 PC1 蛋白成熟功能验证。为了进一步验证，我们在大型外显子组测序的基于人群的队列中鉴定了 功能丧失突变的携带者和非携带者匹配对照，并评估了两组中多囊表型的发生。
临床定义队列中的两名患者具有罕见的功能丧失变体，该基因编码一种蛋白质，该蛋白质对于将特定的甘露糖分子添加到内质网腔中组装的 N-聚糖前体中是必需的。细胞测定表明，的失活导致 PC1 的成熟受损和糖基化缺陷。基于突变携带者状态从基于人群的队列中选择的 8 个病例中的 7 个（88%）在 50 岁后进行了腹部成像，与没有 突变的匹配对照相比，其中 7 个（88%）有至少四个肾囊肿。
是遗传异质性 ADPKD 谱中一个新的疾病基因。这项研究支持在遗传定义的队列中通过表型特征来验证新疾病基因的实用性，并提供急需的基因型-表型相关性。
