Kidney Week

Abstract: TH-OR042

Mutations of DNAJB11 Cause Autosomal Dominant Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Genes, Mechanisms, Interventions
  November 02, 2017 | Location: Room 390, Morial Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Cornec-Le Gall, Emilie, Mayo Clinic, Rochester, United States

Emilie Cornec-Le Gall, MD, PhD



• Gainullin, Vladimir, Mayo Clinic, Rochester, Alabama, United States

Vladimir Gainullin,

• Porath, Binu, Mayo Clinic, Rochester, Alabama, United States

Binu Porath,

• Heyer, Christina M., Mayo Clinic, Rochester, Alabama, United States

Christina M. Heyer,

• Audrezet, Marie-Pierre, University Hospital, Brest, France

Marie-Pierre Audrezet,

• Le Meur, Yannick, University Hospital, Brest, France

Yannick Le Meur,

• Jouret, Francois, University of Liege Hospital (ULg CHU), Liege, Belgium

Francois Jouret,

• Joly, Dominique A, Assistance Publique Hôpitaux de Paris, Paris, France

Dominique A Joly,

• Ferec, Claude, University Hospital, Brest, France

Claude Ferec,

• Yu, Alan S.L., University of Kansas Medical Center, Kansas City, Kansas, United States

Alan S.L. Yu,

• Torres, Vicente E., Mayo Clinic, Rochester, Alabama, United States

Vicente E. Torres,

• Harris, Peter C., Mayo Clinic, Rochester, Alabama, United States

Peter C. Harris,

Background

Seven to 10% of ADPKD patients remain genetically unresolved (GUR). Mutations of GANAB, ALG8 and SEC61B impair polycystin-1 (PC1) maturation and were recently identified in ADPKD or Autosomal Dominant Polycystic Liver Disease families (ADPLD). We hypothesized that other genes processing PC1 may cause ADPKD.

Methods

We performed whole exome sequencing (WES) in a multiplex pedigree and analyzed 600 other GUR families (508 PKD, 92 PLD) by targeted NGS sequencing (TNGS; 55 candidate genes involved in N-linked glycosylation and/or identified by WES). TNGS enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq4000.

Results

WES identified a missense variant (p.P54R) in DNAJB11 in a 78y mother and her 47y daughter, both presenting with unenlarged polycystic kidneys; and CKD4 in the mother (eGFR=28ml/min/1.73m²). DNAJB11 is a protein of the endoplasmic reticulum (ER) functioning as a co-chaperone of BiP, a key player in the control of the protein folding and the regulation of ER stress. p.P54R occurs in the hallmark HPD motif of the highly conserved J domain of the protein, likely disrupting its interaction with BiP. TNGS led to the identification of 3 other DNAJB11 mutations (p.R206*(3), c.479delC(1), p.L77P(1)) in 5 additional families. Ages at diagnosis ranged from 35 to 84y. Clinical presentation was consistent in the 12 affected members (35-92y, 3 males), with normal-sized polycystic kidneys and evolution to kidney atrophy; 5 patients (3 families) reaching ESRD (60y to 92y). Only 5 patients were hypertensive, all after age 50; PLD was mild or absent. Analysis of DNAJB11-/- cells showed a disruption of maturation of polycystin-1 (PC1), while reduced mature PC1 was seen in DNAJB11+/− cells.

Conclusion

Our findings extend the spectrum of genetic causes of ADPKD. DNAJB11 differs from typical ADPKD, with no renal enlargement but progressive tubulointerstitial fibrosis leading to ESRD. In addition to inhibiting PC1 maturation and leading to cystogenesis, mutations of DNAJB11 may inhibit responding appropriately to ER stress in the kidney. Recognizing this further genetic heterogeneity is important since these patients may not benefit from the same therapeutic strategies.

Funding

• NIDDK Support