More dissimilarities than affinities between DNAJB11-PKD and ADPKD

Pisani, Isabella; Allinovi, Marco; Palazzo, Viviana; Zanelli, Paola; Gentile, Micaela; Farina, Maria Teresa; Giuliotti, Sara; Cravedi, Paolo; Delsante, Marco; Maggiore, Umberto; Fiaccadori, Enrico; Manenti, Lucio

doi:10.1093/ckj/sfac032

Cited by 8 publications

(19 citation statements)

References 28 publications

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“…Autosomal-dominant inheritance of inactivating mutations in DNAJB11/ ERdj3 results in a human phenotype of polycystic kidneys and renal failure that is proposed to be an overlap between autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD). 1–4 ADPKD is caused by heterozygous deleterious genetic mutations in the polycystin proteins, PKD1 /PC1 or PKD2 /polycystin-2, that result in an enlarging burden of cysts in both liver and kidneys, large kidneys, and ESKD by the sixth decade on average. 5,6 More mild phenotypes on a spectrum between ADPKD and isolated polycystic liver disease (ADPKD—ADPLD) are caused by mutations in genes— SEC63 , PRKCSH , GANAB , ALG8 , ALG9 , ALG5 , and SEC61B —that encode endoplasmic reticulum (ER) proteins (henceforth referred to as the ER genes) whose loss impairs the maturation of PC1 to its site of function on the surface membrane of the primary cilium.…”

Section: Introductionmentioning

confidence: 99%

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice

Ghosh Roy,

Li,

Guo

et al. 2023

JASN

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Background: Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo. DNAJB11 encodes an Hsp40 co-chaperone in the endoplasmic reticulum (ER): the site of maturation of the ADPKD polycystin-1 (PC1) protein, and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases. Methods: We used germline and conditional alleles to model Dnajb11-kidney disease in mice. In complementary experiments we generated two novel Dnajb11 -/- cell lines that allow assessment of Polycystin-1 (PC1) C-terminal fragment and its ratio to the immature full-length protein. Results: Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11 -/- mice are live-born at below the expected Mendelian ratio and die at weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mice show no evidence of UPR activation nor cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. Conclusions: DNAJB11-kidney disease is on the spectrum of ADPKD phenotypes with a Polycystin-1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.

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Section: Introductionmentioning

confidence: 99%

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice

Ghosh Roy,

Li,

Guo

et al. 2023

JASN

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“…Pancreatic cysts were reported in 1 patient, nephrolithiasis was present in 61.5% of patients, and proteinuria, predominantly albuminuria, was found in various degrees, from mild to nephrotic range. 11 Here, we describe a patient who presented with atypical ADPKD due to a pathogenic variant in DNAJB11, with a few different characteristics compared to what has been described regarding ADPKD due to DNAJB11 variants.…”

Section: Introductionmentioning

confidence: 88%

“…Median age 75 years. 11,12 Reported in individuals between ages 55 and 89 years. 2,11,12 Small cysts, normal kidney size.…”

Section: Dnajb11mentioning

confidence: 99%

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Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

Kachmar,

El-Haffaf,

Bollée

2023

Can J Kidney Health Dis

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Rationale: Due to next-generation sequencing, variants in new genes such as DNAJB11 are recently being identified as causing atypical autosomal dominant polycystic kidney disease (ADPKD). It is important to describe phenotypes associated with these variants in order to increase awareness among clinicians, especially since genetic variability affects ADPKD severity. Presenting Concerns of the Patient: We describe a 55-year-old female patient of Haitian origin who presented with slowly deteriorating kidney function, microscopic hematuria, proteinuria, enlarged kidneys with innumerable small cysts, and a family history of chronic kidney disease and cysts. The phenotype was atypical for ADPKD caused by PKD1 or PKD2 variants, since cysts were of small size, kidneys were only moderately enlarged, and the patient had no extra-renal involvement suggestive of typical ADPKD such as liver cysts, pancreatic cysts, cranial aneurysms, or cardiac abnormalities. Diagnoses: A panel of genes was analyzed by next-generation massive sequencing techniques, including DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, and PKHD1. Genetic testing revealed a heterozygous variant in the DNAJB11 gene (c.123 dup), which is predicted to result in premature protein termination (p. Lys42*) and was classified by the laboratory as likely pathogenic. Interventions: She was treated with candesartan 16 mg once daily to address her proteinuria. Outcomes: At the time of the most recent follow-up, her proteinuria has increased, and her kidney function continues to slowly deteriorate. Teaching Points: DNAJB11 variants are a rare cause of atypical ADPKD. It is important to recognize the clinical features that help distinguish DNAJB11 from PKD1 and PKD2 variants. Atypical ADPKD due to DNAJB11 variants is usually characterized by small cysts, normal kidney size, proteinuria, progressive chronic kidney disease, and phenotypic overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD). It may, however, present itself with enlarged kidneys as was seen in our patient. Genetic testing should be offered whenever a patient presents atypical features of ADPKD, which also requires increased awareness among clinicians regarding the various phenotypes of atypical ADPKD.

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“…The spectrum varies so that the clinical presentation for some families may for example involve more cystic changes, while others present predominantly with CKD and fewer cysts. Pathogenic variants that may present with CKD and cysts include HNF1B (Bleyer et al, 2021 ; Bleyer & Kmoch, 2020 ; Kolbuc et al, 2020 ; Okorn et al, 2019 ), DNAJB11 (Huynh et al, 2020 ; Pisani et al, 2022 ; Senum et al, 2022 ), ALG5 (Lemoine et al, 2022 ), and IFT140 (Senum et al, 2022 ). Similarly, patients with congenital anomalies of the kidney and urinary tract (CAKUT) due to JAG1 (Spinner, Gilbert, Loomes, & Krantz, 1993 ), NOTCH2 (Kamath et al, 2012 ), SALL1 (Reardon et al, 2007 ), and GATA3 (Lemos & Thakker, 2020 ; Upadhyay et al, 2013 ) mutations may present in adulthood with CKD.…”

Section: Other Autosomal Dominant Tubulointerstitial Kidney Diseasesmentioning

confidence: 99%

Autosomal dominant tubulointerstitial kidney disease: A review

Živná

Kidd

Barešová

et al. 2022

American J of Med Genetics Pt C

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The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD‐UMOD is also associated with hyperuricemia and gout. ADTKD‐REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD‐MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.

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More dissimilarities than affinities between DNAJB11-PKD and ADPKD

Cited by 8 publications

References 28 publications

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice

Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

Autosomal dominant tubulointerstitial kidney disease: A review

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