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Publication Information
Affiliation
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Nephrology, University Hospital, European University of Brittany, Brest, Brittany 29200, France; Department of Molecular Genetics, National Institute of Health and Medical Sciences, INSERM U1078, Brest 29200, France.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.; Section of Nephrology, Yale School of Medicine, New Haven, CT 06520, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Department of Molecular Genetics, National Institute of Health and Medical Sciences, INSERM U1078, Brest 29200, France.; Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80202, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology, University Health Network, Toronto, ON M5G 2C4, Canada.; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Department of Molecular Genetics, National Institute of Health and Medical Sciences, INSERM U1078, Brest 29200, France.; Service of Nephrology, Necker Hospital, Paris 75231, France.; Division of Nephrology, University of Liège, Liège 4000, Belgium.; Service of Nephrology and Hemodialysis, Saintes 17108, France.; Service of Nephrology, Yves Le Foll Hospital, Saint Brieuc 22000, France.; Service of Nephrology, Yves Le Foll Hospital, Saint Brieuc 22000, France.; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA.; Department of Medical Imaging, University Health Network, Toronto, ON M5G 2C4, Canada.; Division of Nephrology, University Health Network, Toronto, ON M5G 2C4, Canada.; Section of Nephrology, Yale School of Medicine, New Haven, CT 06520, USA.; Department of Nephrology, University Hospital, European University of Brittany, Brest, Brittany 29200, France.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: harris.peter@mayo.edu.
Authors
Cornec-Le Gall Emilie, Olson Rory J., Besse Whitney, Heyer Christina M., Gainullin Vladimir G., Smith Jessica M., Audrézet Marie-Pierre, Hopp Katharina, Porath Binu, Shi Beili, Baheti Saurabh, Senum Sarah R., Arroyo Jennifer, Madsen Charles D., Férec Claude, Joly Dominique, Jouret François, 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.
Studies
Abstract
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.