An international cohort study of autosomal dominant tubulointerstitial kidney disease due to   mutations identifies distinct clinical subtypes

Živná, Martina; Kidd, Kendrah; Zaidan, Mohamad; Vyleťal, Petr; Barešová, Veronika; Hodaňová, Kateřina; Sovová, Jana; Hartmannová, Hana; Votruba, Miroslav; Trešlová, Helena; Jedličková, Ivana; Sikora, Jakub; Hůlková, Helena; Robins, Victoria; Hnı́zda, Aleš; Živný, J; Papagregoriou, Gregory; Mesnard, Laurent; Beck, Bodo B.; Wenzel, Andrea; Tory, Kálmán; Häeffner, Karsten; Wolf, Matthias; Bleyer, Michael E.; Sayer, John A.; Ong, Albert; Balogh, Lídia; Jakubowska, Anna; Laszkiewicz, Agnieszka; Clissold, Rhian L; Shaw‐Smith, Charles; Munshi, Raj; Haws, Robert; Izzi, Claudia; Capelli, Irene; Santostefano, Marisa; Graziano, Claudio; Scolari, Francesco; Sussman, Amy; Trachtman, Howard; Decramer, Stéphane; Matignon, Marie; Grimbert, Philippe; Shoemaker, Lawrence; Stavrou, Christoforos; Abdelwahed, Mayssa; Belghith, Neila; Sinclair, Matthew; Claes, Kathleen; Kopel, Tal; Moe, Sharon M.; Deltas, Constantinos; Knebelmann, Bertrand; Rampoldi, Luca; Kmoch, Stanislav; Bleyer, Anthony J.

doi:10.1016/j.kint.2020.06.041

Cited by 28 publications

(42 citation statements)

References 36 publications

(48 reference statements)

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“…However, a recent international cohort study on clinical characteristics of 111 ADTKD-REN patients reported that approximately 70% of the patients presented to medical institutions for CKD or gout. 21 According to this report, childhood anemia was present in 75.8% of the patients but its severity was relatively mild; mean hemoglobin levels were 9.6, 10.1, and 10.5 g/dL for age <10 years, 10 to <15 years, and 15 to <20 years, respectively. 21 Although hypotension was not reported in the article, the severity of hyperkalemia was mild and the mean serum potassium level in patients who were not taking fludrocortisone was 4.8 mEq/L.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 80%

“…21 According to this report, childhood anemia was present in 75.8% of the patients but its severity was relatively mild; mean hemoglobin levels were 9.6, 10.1, and 10.5 g/dL for age <10 years, 10 to <15 years, and 15 to <20 years, respectively. 21 Although hypotension was not reported in the article, the severity of hyperkalemia was mild and the mean serum potassium level in patients who were not taking fludrocortisone was 4.8 mEq/L. 21 Childhood anemia, hypotension, or hyperkalemia may often be overlooked and are not always specific to ADRKD-REN; thus, we did not exclude participants with these findings.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 80%

“…21 Although hypotension was not reported in the article, the severity of hyperkalemia was mild and the mean serum potassium level in patients who were not taking fludrocortisone was 4.8 mEq/L. 21 Childhood anemia, hypotension, or hyperkalemia may often be overlooked and are not always specific to ADRKD-REN; thus, we did not exclude participants with these findings. ADTKD-SEC61A1 is much rarer than other ADTKD subtypes, with six families reported as of date.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 94%

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Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease

Okada

Morisada

Horinouchi

et al. 2022

Kidney International Reports

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 80%

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 80%

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 94%

See 1 more Smart Citation

Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease

Okada

Morisada

Horinouchi

et al. 2022

Kidney International Reports

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“…Uromodulin showed an impaired transport specifically in presence of the V67G mutations ( Fig 3A and B ). This finding was further supported by testing kidney disease-associated variants of renin and uromodulin ( Vylet’al et al, 2006 ; Williams et al, 2009 ; Živná et al, 2009 ; Beck et al, 2011 ; Olinger et al, 2020 ; Živná et al, 2020 ). Like their wild-type counterparts, the W10R mutant of renin and the C32Y mutant of uromodulin showed impaired transport in presence of both ADTKD– SEC61A1 mutations or just the V67G mutation, respectively ( Fig S4E ).…”

Section: Resultsmentioning

confidence: 80%

“…To identify the substrate-specific determinant that contributes to the impaired protein transport in ADTKD– SEC61A1 cells, we focused on the signal peptide of renin. To date, multiple dominant mutations (e.g., W10R, L16R, and C20R) in the signal peptide of renin have been found to cause ADTKD– REN , adhering to the gene-based terminology ( Živná et al, 2009 , 2020 ; Bleyer et al, 2010 ; Beck et al, 2011 ). Therefore, we replaced the signal peptide of renin by a signal peptide similar in length of the unaffected, soluble substrate preproapelin giving rise to the APE–REN construct.…”

Section: Resultsmentioning

confidence: 99%

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

et al. 2022

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The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD–SEC61A1). Using cellular disease models for ADTKD–SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD–SEC61A1 patients as well.

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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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An international cohort study of autosomal dominant tubulointerstitial kidney disease due to mutations identifies distinct clinical subtypes

Cited by 28 publications

References 36 publications

Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease

Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

Autosomal dominant tubulointerstitial kidney disease: A review

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