Reference : Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney ...
Scientific journals : Article
Human health sciences : Urology & nephrology
http://hdl.handle.net/2268/223539
Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.
English
Cornec-Le Gall, Emilie [> >]
Olson, Rory J. [> >]
Besse, Whitney [> >]
Heyer, Christina M. [> >]
Gainullin, Vladimir G. [> >]
Smith, Jessica M. [> >]
Audrezet, Marie-Pierre [> >]
Hopp, Katharina [> >]
Porath, Binu [> >]
Shi, Beili [> >]
Baheti, Saurabh [> >]
Senum, Sarah R. [> >]
Arroyo, Jennifer [> >]
Madsen, Charles D. [> >]
Ferec, Claude [> >]
Joly, Dominique [> >]
Jouret, François mailto [Université de Liège - ULiège > Département des sciences cliniques > Néphrologie >]
Fikri-Benbrahim, Oussamah [> >]
Charasse, Christophe [> >]
Coulibaly, Jean-Marie [> >]
Yu, Alan S. [> >]
Khalili, Korosh [> >]
Pei, York [> >]
Somlo, Stefan [> >]
Le Meur, Yannick [> >]
Torres, Vicente E. [> >]
Harris, Peter C. [> >]
2018
American Journal of Human Genetics
102
5
832-844
Yes (verified by ORBi)
International
0002-9297
1537-6605
United States
[en] ADPKD ; ADPLD ; ADTKD ; DNAJB11 ; pathogenic variants ; renal cystic disease
[en] 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 approximately 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.
http://hdl.handle.net/2268/223539
10.1016/j.ajhg.2018.03.013
Copyright (c) 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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