期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 102, 期 5, 页码 832-844出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2018.03.013
关键词
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资金
- NIDDK [DK058816, DK056943, DK056956, DK056957, DK056961, DK062410, DK062408, DK062402, DK082230, DK062411, DK062401]
- Mayo Translational PKD Center [DK090728]
- American Society of Nephrology (ASN) Foundation Kidney Research Fellowship
- Fulbright Association
- Foundation Monaham
- PKD Foundation fellowship
- American Heart Association postdoctoral fellowship
- ASN Ben J. Lipps Fellowship
- NIDDK Predoctoral Studentships
- Mayo Graduate School
- Zell Family Foundation
- Belgian Fonds National de la Recherche Scientifique
- National Center for Research Resources General Clinical Research Centers
- National Center for Advancing Translational Sciences Clinical and Translational Science Awards
- National Plans for Clinical Research
- Groupement Interregional de Recherche Clinique et d'Innovation (GIRCI Grand Ouest)
- French Society of Nephrology
- National Human Genome Research Institute [UM1 HG006504]
- National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program
- Yale O'Brien Kidney Center [P30 DK079310]
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.
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