Korosh Khalili, Marie-Pierre Audrézet, Stefan Somlo, Oussamah Fikri-Benbrahim, Katharina Hopp, Jessica M. Smith, François Jouret, Saurabh Baheti, Claude Férec, Christina M. Heyer, Peter C. Harris, Dominique Joly, Binu Porath, Sarah R. Senum, Charles D. Madsen, Christophe Charasse, Yannick Le Meur, Jennifer Arroyo, Beili Shi, Whitney Besse, York Pei, Vladimir G. Gainullin, Emilie Cornec-Le Gall, Alan S.L. Yu, Vicente E. Torres, Jean-Marie Coulibaly, Rory J. Olson, Service de Nephrologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Department of Biochemistry and Molecular Biology, Mayo Clinic, Yale University School of Medicine, Division of Nephrology and Hypertension, Mayo Clinic [Rochester], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Nephrology, Toronto (University Health Network), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Évolution, génomes, comportement et écologie (EGCE), Centre National de la Recherche Scientifique (CNRS)-IRD-Université Paris-Sud - Paris 11 (UP11), Division of Nephrology, Liège, Service of Nephrology and Hemodialysis, Saintes, CH de Saint-Brieuc, Service de Néphrologie, CH St Brieuc, Institute of Geology and Geophysics [Beijing] (IGG), Chinese Academy of Sciences [Beijing] (CAS), Department of Medical Imaging [University of Toronto], University of Toronto, Divisions of Nephrology and Genomic Medicine, University of Toronto-University Health Network, Department of Internal Medicine, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Universidade de Aveiro, Department of Computer Science and Software Engineering (CCSE), University of Melbourne, Université Paris-Sud - Paris 11 (UP11)-IRD-Centre National de la Recherche Scientifique (CNRS), and Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)
International audience; 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 ∼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.