Uromodulin processing in DNAJB11-kidney disease

Mariniello, Marta; Schiano, Guglielmo; Yoshifuji, Ayumi; Gillion, Valentine; Sayer, John Andrew; Jouret, François; Le Meur, Yannick; Cornec-Le Gall, Emilie; Olinger, Eric Gregory; Devuyst, Olivier

doi:10.1016/j.kint.2023.11.008

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…S4). This finding is supported by a recent study questioning the involvement of uromodulin in DNAJB11-dependent kidney disease based on data measuring urinary uromodulin levels and its trafficking in renal epithelial cells (47). Furthermore, we did not find evidence for an involvement of the TAL in cyst formation or fibrosis.…”

Section: Discussionsupporting

confidence: 89%

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Busch,

Neubauer,

Schmitt

et al. 2024

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes PKD1 and PKD2, encoding the membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 form a receptor-ion channel complex that is required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation from epithelial cells of all nephron segments. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through pathogenic mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an endoplasmic reticulum (ER) co-chaperone associated with atypical ADPKD. Mouse models with constitutive and conditional Dnajb11 inactivation as well as Dnajb11-deficient renal epithelial cells were generated to investigate the genetic mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation influences disease severity. Furthermore, impaired PC1 cleavage is identified as a potential mechanism underlying DNAJB11-dependent cyst formation. Quantitative proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, which may help to better understand phenotypic differences between different forms of ADPKD.

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Section: Discussionsupporting

confidence: 89%

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Busch,

Neubauer,

Schmitt

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

The role of the co‐chaperone DNAJB11 in polycystic kidney disease: Molecular mechanisms and cellular origin of cyst formation

Busch,

Neubauer,

Schmitt

et al. 2024

The FASEB Journal

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2, encoding polycystin‐1 (PC1) and polycystin‐2 (PC2), which are required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)‐resident proteins through mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an ER co‐chaperone associated with atypical ADPKD. We generated mouse models with constitutive and conditional Dnajb11 inactivation and Dnajb11‐deficient renal epithelial cells to investigate the mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11‐dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11‐dependent cyst formation. Proteomic analysis of Dnajb11‐ and Pkd1‐deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD.

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DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort

Aiello,

Ciurli,

Conti

et al. 2023

Genes

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.

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Uromodulin processing in DNAJB11-kidney disease

Cited by 3 publications

References 10 publications

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

The role of the co‐chaperone DNAJB11 in polycystic kidney disease: Molecular mechanisms and cellular origin of cyst formation

DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort

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