Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney 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.

Disciplines :

Urology & nephrology

Author, co-author :

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

More authors (17 more)

Language :

English

Title :

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

Publication date :

2018

Journal title :

American Journal of Human Genetics

ISSN :

0002-9297

eISSN :

1537-6605

Publisher :

University of Chicago Press, United States - Illinois

Volume :

102

Issue :

Pages :

832-844

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 18 May 2018

Statistics

Number of views

77 (17 by ULiège)

Number of downloads

11 (9 by ULiège)

More statistics

Scopus citations^®

192

Scopus citations^®
without self-citations

146

OpenCitations

162

Bibliography

Ong, A.C., Devuyst, O., Knebelmann, B., Walz, G., Diseases, ERA-EDTA Working Group for Inherited Kidney Diseases. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet 385 (2015), 1993–2002.
The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77 (1994), 881–894.
Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S.L., Veldhuisen, B., Saris, J.J., Reynolds, D.M., Cai, Y., Gabow, P.A., Pierides, A., et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272 (1996), 1339–1342.
Heyer, C.M., Sundsbak, J.L., Abebe, K.Z., Chapman, A.B., Torres, V.E., Grantham, J.J., Bae, K.T., Schrier, R.W., Perrone, R.D., Braun, W.E., et al., HALT PKD and CRISP Investigators. Predicted mutation strength of nontruncating PKD1 mutations aids genotype-phenotype correlations in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 27 (2016), 2872–2884.
Cornec-Le Gall, E., Audrézet, M.P., Chen, J.M., Hourmant, M., Morin, M.P., Perrichot, R., Charasse, C., Whebe, B., Renaudineau, E., Jousset, P., et al. Type of PKD1 mutation influences renal outcome in ADPKD. J. Am. Soc. Nephrol. 24 (2013), 1006–1013.
Besse, W., Dong, K., Choi, J., Punia, S., Fedeles, S.V., Choi, M., Gallagher, A.R., Huang, E.B., Gulati, A., Knight, J., et al. Isolated polycystic liver disease genes define effectors of polycystin-1 function. J. Clin. Invest. 127 (2017), 1772–1785.
Porath, B., Gainullin, V.G., Cornec-Le Gall, E., Dillinger, E.K., Heyer, C.M., Hopp, K., Edwards, M.E., Madsen, C.D., Mauritz, S.R., Banks, C.J., et al. Genkyst Study Group, HALT Progression of Polycystic Kidney Disease Group, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. Mutations in GANAB, encoding the glucosidase IIα subunit, cause autosomal-dominant polycystic kidney and liver disease. Am. J. Hum. Genet. 98 (2016), 1193–1207.
Besse, W., Choi, J., Ahram, D., Mane, S., Sanna-Cherchi, S., Torres, V., Somlo, S., A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family. Hum. Mutat. 39 (2018), 378–382.
Cornec-Le Gall, E., Torres, V.E., Harris, P.C., Genetic complexity of autosomal dominant polycystic kidney and liver diseases (ADPKD and ADPLD). J. Am. Soc. Nephrol. 29 (2018), 13–23.
Rossetti, S., Consugar, M.B., Chapman, A.B., Torres, V.E., Guay-Woodford, L.M., Grantham, J.J., Bennett, W.M., Meyers, C.M., Walker, D.L., Bae, K., et al., CRISP Consortium. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 18 (2007), 2143–2160.
Cornec-Le Gall, E., Audrézet, M.P., Rousseau, A., Hourmant, M., Renaudineau, E., Charasse, C., Morin, M.P., Moal, M.C., Dantal, J., Wehbe, B., et al. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 27 (2016), 942–951.
Ong, A.C., Harris, P.C., A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int. 88 (2015), 699–710.
Gainullin, V.G., Hopp, K., Ward, C.J., Hommerding, C.J., Harris, P.C., Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner. J. Clin. Invest. 125 (2015), 607–620.
Hopp, K., Ward, C.J., Hommerding, C.J., Nasr, S.H., Tuan, H.F., Gainullin, V.G., Rossetti, S., Torres, V.E., Harris, P.C., Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J. Clin. Invest. 122 (2012), 4257–4273.
Eckardt, K.U., Alper, S.L., Antignac, C., Bleyer, A.J., Chauveau, D., Dahan, K., Deltas, C., Hosking, A., Kmoch, S., Rampoldi, L., et al., Kidney Disease: Improving Global Outcomes. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management–A KDIGO consensus report. Kidney Int. 88 (2015), 676–683.
Devuyst, O., Olinger, E., Rampoldi, L., Uromodulin: from physiology to rare and complex kidney disorders. Nat. Rev. Nephrol. 13 (2017), 525–544.
Quaglia, M., Musetti, C., Ghiggeri, G.M., Fogazzi, G.B., Settanni, F., Boldorini, R.L., Lazzarich, E., Airoldi, A., Izzo, C., Giordano, M., Stratta, P., Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy. Clin. Transplant. 28 (2014), 995–1003.
Schrier, R.W., Abebe, K.Z., Perrone, R.D., Torres, V.E., Braun, W.E., Steinman, T.I., Winklhofer, F.T., Brosnahan, G., Czarnecki, P.G., Hogan, M.C., et al., HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N. Engl. J. Med. 371 (2014), 2255–2266.
Torres, V.E., Abebe, K.Z., Chapman, A.B., Schrier, R.W., Braun, W.E., Steinman, T.I., Winklhofer, F.T., Brosnahan, G., Czarnecki, P.G., Hogan, M.C., et al., HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N. Engl. J. Med. 371 (2014), 2267–2276.
Hwang, Y.H., Conklin, J., Chan, W., Roslin, N.M., Liu, J., He, N., Wang, K., Sundsbak, J.L., Heyer, C.M., Haider, M., et al. Refining genotype-phenotype correlation in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 27 (2016), 1861–1868.
Iliuta, I.A., Kalatharan, V., Wang, K., Cornec-Le Gall, E., Conklin, J., Pourafkari, M., Ting, R., Chen, C., Borgo, A.C., He, N., et al. Polycystic kidney disease without an apparent family history. J. Am. Soc. Nephrol. 28 (2017), 2768–2776.
Grantham, J.J., Torres, V.E., Chapman, A.B., Guay-Woodford, L.M., Bae, K.T., King, B.F. Jr., Wetzel, L.H., Baumgarten, D.A., Kenney, P.J., Harris, P.C., et al., CRISP Investigators. Volume progression in polycystic kidney disease. N. Engl. J. Med. 354 (2006), 2122–2130.
Levey, A.S., Stevens, L.A., Schmid, C.H., Zhang, Y.L., Castro, A.F. 3rd, Feldman, H.I., Kusek, J.W., Eggers, P., Van Lente, F., Greene, T., Coresh, J., CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150 (2009), 604–612.
Shen, Y., Meunier, L., Hendershot, L.M., Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress. J. Biol. Chem. 277 (2002), 15947–15956.
Shen, Y., Hendershot, L.M., ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. Mol. Biol. Cell 16 (2005), 40–50.
Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks, E., Fennell, T., O'Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B., et al., Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536 (2016), 285–291.
Chapman, A.B., Bost, J.E., Torres, V.E., Guay-Woodford, L., Bae, K.T., Landsittel, D., Li, J., King, B.F., Martin, D., Wetzel, L.H., et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 7 (2012), 479–486.
Pei, Y., Obaji, J., Dupuis, A., Paterson, A.D., Magistroni, R., Dicks, E., Parfrey, P., Cramer, B., Coto, E., Torra, R., et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J. Am. Soc. Nephrol. 20 (2009), 205–212.
Pei, Y., Hwang, Y.H., Conklin, J., Sundsbak, J.L., Heyer, C.M., Chan, W., Wang, K., He, N., Rattansingh, A., Atri, M., et al. Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 26 (2015), 746–753.
Rahbari-Oskoui, F., O'Neill, W.C., Diagnosis and management of acquired cystic kidney disease and renal tumors in ESRD patients. Semin. Dial. 30 (2017), 373–379.
Inagi, R., Ishimoto, Y., Nangaku, M., Proteostasis in endoplasmic reticulum–new mechanisms in kidney disease. Nat. Rev. Nephrol. 10 (2014), 369–378.
Wang, M., Kaufman, R.J., Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529 (2016), 326–335.
Cabezas, O.R., Flanagan, S.E., Stanescu, H., García-Martínez, E., Caswell, R., Lango-Allen, H., Antón-Gamero, M., Argente, J., Bussell, A.M., Brandli, A., et al. Polycystic kidney disease with hyperinsulinemic hypoglycemia caused by a promoter mutation in phosphomannomutase 2. J. Am. Soc. Nephrol. 28 (2017), 2529–2539.
Bolar, N.A., Golzio, C., Živná, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J.R., Raes, A., et al. Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia. Am. J. Hum. Genet. 99 (2016), 174–187.
Kimura, K., Jin, H., Ogawa, M., Aoe, T., Dysfunction of the ER chaperone BiP accelerates the renal tubular injury. Biochem. Biophys. Res. Commun. 366 (2008), 1048–1053.
Genereux, J.C., Qu, S., Zhou, M., Ryno, L.M., Wang, S., Shoulders, M.D., Kaufman, R.J., Lasmézas, C.I., Kelly, J.W., Wiseman, R.L., Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J. 34 (2015), 4–19.
Wang, M., Kaufman, R.J., The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer 14 (2014), 581–597.
Zhang, L.H., Yang, X.L., Zhang, X., Cheng, J.X., Zhang, W., Association of elevated GRP78 expression with increased astrocytoma malignancy via Akt and ERK pathways. Brain Res. 1371 (2011), 23–31.