Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

Wopperer, Florian J.; Knaup, Karl X.; Stanzick, Kira J.; Schneider, Karen; Jobst-Schwan, Tilman; Ekici, Arif B.; Uebe, Steffen; Wenzel, Andrea; Schliep, Stefan; Schürfeld, Carsten; Seitz, Randolf; Bernhardt, Wanja M.; Gödel, Markus; Wiesener, Antje; Popp, Bernt; Stark, Klaus; Gröne, Hermann–Josef; Friedrich, Björn; Weiss, Martin H.; Bašić‐Jukić, Nikolina; Schiffer, Mario; Schröppel, Bernd; Huettel, Bruno; Beck, Bodo B.; Sayer, John A.; Ziegler, Christine; Büttner‐Herold, Maike; Amann, Kerstin; Heid, Iris M.; Reis, André; Pasutto, Francesca; Wiesener, Michael S.

doi:10.1016/j.kint.2022.04.031

Cited by 13 publications

(9 citation statements)

References 66 publications

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“…Wopperer et al. 19 performed exome sequencing in 16 families with ADTKD with no sequence variant found (including MUC1 ), of which 9 showed diagnostic variants in the nephrome (4 in COL4A5 , 2 in INF2 , and 1 each in COL4A4 , PAX2 , SALL1 , and PKD2 ). Nephronophthisis (1 NPHP1 , 1 NPHP4 , and 1 TTC21B found in our study) may also be a differential diagnosis of ADTKD in young adults; however usually, autosomal recessive inheritance distinguishes it from ADTKD.…”

Section: Discussionmentioning

confidence: 99%

Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection

Fages,

Bourre,

Larrue

et al. 2024

Kidney International Reports

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Section: Discussionmentioning

confidence: 99%

Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection

Fages,

Bourre,

Larrue

et al. 2024

Kidney International Reports

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“…We also queried annotation data for the 5,906 genes (“gene-to-phenotype mapping”): (4) whether the gene had kidney-relevant phenotypes in mice (Mouse Genome Informatics, MGI [ 20 ]); (5) whether the gene was known for human genetic disorders with kidney phenotype (Online Mendelian Inheritance in Man, OMIM, [ 21 ]) or with evidence from sequencing patients (CKD patients [ 22 ] or autosomal dominant tubulointerstitial kidney disease patients [ 23 ]); (6) whether the gene was known for drugability or drug-interaction from registered clinical trials (Therapeutic Target Database [ 24 ]) for kidney-related indications (ICD-11 codes GB4“X” to GB9“X”, Additional file 1 : Table S1), also providing the information on other indications (relevant for re-purposing).…”

Section: Construction and Contentmentioning

confidence: 99%

“…A: Separating the variants by strength of statistical support, we show the number of variants that are protein-relevant [ 11 , 16 ] or an eQTL/sQTL [ 17 – 19 ] in kidney tissue, the number of signals, and the number of mapped genes. B: Shown are the number of genes known for (i) causing a genetic disorder in human with kidney phenotype [ 21 – 23 ], (ii) a kidney phenotype in mouse [ 20 ] (iii) being drug target in registered clinical trials for kidney disease or any other diseases [ 24 ] Columns: “PPA > 99%”: exactly one variant in credible set; “PPA 50–99%”: variant has high PPA; “other variants in small set”: variant in small set that has PPA > < 50%; “any other variants”: variants with PPA > < 50% and set size > 5); Abbreviations: VEP: Variant effect predictor, CADD-Phred: Score for deleteriousness of a variant, eQTL: expression quantitative trait locus, sQTL: splice quantitative trait locus, #sig: number of signals, #var: number of variants in 99% credible sets CKD chronic kidney disease, ADTKD autosomal dominant tubulointerstitial kidney disease, MGI mouse genome informatics, TTD therapeutic target database…”

Section: Construction and Contentmentioning

confidence: 99%

KidneyGPS: a user-friendly web application to help prioritize kidney function genes and variants based on evidence from genome-wide association studies

Stanzick,

Stark,

Gorski

et al. 2023

BMC Bioinformatics

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Background Genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with kidney function. By combining these findings with post-GWAS information (e.g., statistical fine-mapping to identify independent association signals and to narrow down signals to causal variants; or different sources of annotation data), new hypotheses regarding physiology and disease aetiology can be obtained. These hypotheses need to be tested in laboratory experiments, for example, to identify new therapeutic targets. For this purpose, the evidence obtained from GWAS and post-GWAS analyses must be processed and presented in a way that they are easily accessible to kidney researchers without specific GWAS expertise. Main Here we present KidneyGPS, a user-friendly web-application that combines genetic variant association for estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics consortium with annotation of (i) genetic variants with functional or regulatory effects (“SNP-to-gene” mapping), (ii) genes with kidney phenotypes in mice or human (“gene-to-phenotype”), and (iii) drugability of genes (to support re-purposing). KidneyGPS adopts a comprehensive approach summarizing evidence for all 5906 genes in the 424 GWAS loci for eGFR identified previously and the 35,885 variants in the 99% credible sets of 594 independent signals. KidneyGPS enables user-friendly access to the abundance of information by search functions for genes, variants, and regions. KidneyGPS also provides a function (“GPS tab”) to generate lists of genes with specific characteristics thus enabling customizable Gene Prioritisation (GPS). These specific characteristics can be as broad as any gene in the 424 loci with a known kidney phenotype in mice or human; or they can be highly focussed on genes mapping to genetic variants or signals with particularly with high statistical support. KidneyGPS is implemented with RShiny in a modularized fashion to facilitate update of input data (https://kidneygps.ur.de/gps/). Conclusion With the focus on kidney function related evidence, KidneyGPS fills a gap between large general platforms for accessing GWAS and post-GWAS results and the specific needs of the kidney research community. This makes KidneyGPS an important platform for kidney researchers to help translate in silico research results into in vitro or in vivo research.

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“…ADTKD‐ MUC1 is always caused by pathogenic variants that result in the creation of the +1 frameshift MUC1 protein (MUC1fs), The most common pathogenic variant causing ADTKD‐ MUC1 is the insertion of an extra cytosine within a heptanucleotide cytosine tract that is found in each VNTR unit (Kirby et al, 2013 ; Wopperer et al, 2022 ). MUC1fs as a high positive charge (pI) and deposits within the endoplasmic reticulum Golgi intermediate compartment (ERGIC) (Dvela‐Levitt et al, 2019 ).…”

Section: Adtkd‐muc1mentioning

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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Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases

Cited by 13 publications

References 66 publications

Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection

Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection

KidneyGPS: a user-friendly web application to help prioritize kidney function genes and variants based on evidence from genome-wide association studies

Autosomal dominant tubulointerstitial kidney disease: A review

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