Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease
Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease
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DOI：
10.1016/j.ajhg.2018.03.013
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发表时间：
2018-05-03
影响因子：
9.8
通讯作者：
Harris, Peter C.
中科院分区：
文献类型：
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作者：
Cornec-Le Gall, Emilie;Olson, Rory J.;Harris, Peter C.
常染色体显性多囊肾病（ADPKD）的特征是肾囊肿的进行性发展，通常导致终末期肾病（ESRD）。这种疾病在遗传上是异质的，大约有7%的家庭在遗传上没有得到解决。我们在两个多重ADPKD样家系中进行了全外显子组测序（WES），并通过对65个候选基因进行靶向下一代测序，进一步分析了591个遗传学未解决的表型相似的家族。WES在两个家族成员中发现了一个DNAJB 11错义变体（p.Pro54Arg），表现为非扩大的多囊肾，在第二个家族中发现了一个移码变化（c.166_167insTT），表现为小的肾囊肿和肝囊肿。DNAJB 11是BiP的辅因子，BiP是内质网中控制分泌蛋白和膜蛋白的折叠、运输和降解的关键伴侣。通过靶向分析确定了另外五个携带DNAJB 11突变的多代家庭。临床表型在23名受影响的成员中是一致的，非扩大的囊性肾通常演变为肾萎缩; 7名受试者在59至89岁之间达到ESRD。肾脏不肿大、非囊性实质组织学上明显的间质纤维化和痛风复发（一个家族）提示与常染色体显性肾小管间质疾病（ADTKD）有部分表型重叠。DNAJB 11-null细胞和受影响个体的肾脏样本的表征揭示了与涉及ADPKD蛋白、PC 1和ADTKD蛋白（如UMOD）的成熟和运输缺陷相关的发病机制。DNAJB 11相关疾病是ADPKD和ADTKD的表型杂交体，其特征在于正常大小的囊性肾和导致迟发性ESRD的进行性间质纤维化。
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with similar to 7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.