High-throughput Mutationsanalyse für bekannte und neuartige monogene Nierensteinleiden und verwandte Störungen
Humangenetik
Reproduktionsmedizin, Urologie
Zusammenfassung der Projektergebnisse
The aim of this DFG-project was the identification and characterization of monogenic disorders leading to kidney stone formation, nephrocalcinosis, and other disorders of tubular dysfunction. As part of the project, we were able to establish an international patient registry for hereditary nephrolithiasis and nephrocalcinosis building the basis of current and future research in this field. On a functional level, the focus of our investigations concerned renal phosphate wasting (NaPis) and cystinuria. While in renal phosphate wasting, we demonstrated pathogenicity of a frequent SLC34A3 (NaPi2c) variant in European carries, in cystinuria, an international cohort allowed us to identify novel genotype-phenotype correlations pointing towards increased disease severity upon multiallelism. In the field of gene discovery, we identified CLDN10-variants as the cause of a novel salt-losing tubulopathy with extrarenal manifestations in terms of hypohidrosis, electrolyte imbalances, hypolacrimia, ichthyosis, xerostomia, and amelogenesis imperfecta (HELIX-syndrome). Furthermore, we found SLC7A13/AGT1-variants to likely influence disease severity in cystinuric patients and demonstrated pathogenicity via a newly established functional assay. In addition, this project also enabled accomplishment of related work on renal ciliopathies, namely nephronophthisis (NPHP20 / MAPKBP1) and ADPKD, generating novel insights into disease mechanisms of these hereditary tubular disorders.
Projektbezogene Publikationen (Auswahl)
- Kidney Int. 2018 Jan;93(1):204-213
Daga A, Majmundar AJ, Braun DA, Gee HY, Lawson JA, Shril S, Jobst-Schwan T, Vivante A, Schapiro D, Tan W, Warejko JK, Widmeier E, Nelson CP, Fathy HM, Gucev Z, Soliman NA, Hashmi S, Halbritter J, Halty M, Kari JA, El-Desoky S, Ferguson MA, Somers MJG, Traum AZ, Stein DR, Daouk GH, Rodig NM, Katz A, Hanna C, Schwaderer AL, Sayer JA, Wassner AJ, Mane S, Lifton RP, Milosevic D, Tasic V, Baum MA, Hildebrandt F
(Siehe online unter https://doi.org/10.1016/j.kint.2017.06.025) - Update on Hereditary Kidney Stone Disease and Introduction of a New Clinical Patient Registry in Germany. Front Pediatr. 2018 Mar 7;6:47
Halbritter J, Seidel A, Müller L, Schönauer R, Hoppe B
(Siehe online unter https://doi.org/10.3389/fped.2018.00047) - Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting. Urolithiasis. 2019 Feb 23
Schönauer R, Petzold F, Lucinescu W, Seidel A, Müller L, Neuber S, Bergmann C, Sayer JA, Werner A, Halbritter J
(Siehe online unter https://doi.org/10.1007/s00240-019-01116-2) - Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. Hum Genet. 2019 Mar;138(3):211-219
Amar A, Majmundar AJ, Ullah I, Afzal A, Braun DA, Shril S, Daga A, Jobst-Schwan T, Ahmad M, Sayer JA, Gee HY, Halbritter J, Knöpfel T, Hernando N, Werner A, Wagner C, Khaliq S, Hildebrandt F
(Siehe online unter https://doi.org/10.1007/s00439-019-01978-x) - Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease. Kidney Int. 2019 Jul;96(1):222-230
Ottlewski I, Münch J, Wagner T, Schönauer R, Bachmann A, Weimann A, Hentschel J, Lindner TH, Seehofer D, Bergmann C, Jamra RA, Halbritter J
(Siehe online unter https://doi.org/10.1016/j.kint.2019.01.038) - Autosomal Dominant Polycystic Kidney Disease in Absence of Renal Cyst Formation Illustrates Genetic Interaction Between WT1 and PKD1. J Med Genet. 2020 May 7:jmedgenet-2019-106633
Münch J, Kirschner KM, Schlee H, Kraus C, Schönauer R, Le Duc GD, Scholz H, Halbritter J
(Siehe online unter https://doi.org/10.1136/jmedgenet-2019-106633) - Matching Clinical and Genetic Diagnoses in Autosomal Dominant Polycystic Kidney Disease Reveals Novel Phenocopies and Potential Candidate Genes. Genet Med. 2020 May 13
Schönauer R, Baatz S, Nemitz-Kliemchen M, Frank V, Petzold F, Sewerin S, Popp B, Münch J, Neuber S, Bergmann C, Halbritter J
(Siehe online unter https://doi.org/10.1038/s41436-020-0816-3) - Novel Nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment. Kidney Int. 2020 Jun 4:S0085- 2538(20)30632-3
Schönauer R, Jin W, Ertel A, Nemitz-Kliemchen M, Panitz N, Hantmann E, Seidel A, Braun DA, Shril S, Hansen M, Shahzad K, Sandford R, Saunier S, Benmerah A, Bergmann C, Hildebrandt F, Halbritter J
(Siehe online unter https://doi.org/10.1016/j.kint.2020.05.027) - Metabolic Nephropathy Workgroup of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN. Cystinuria: clinical practice recommendation. Kidney Int. 2021 Jan;99(1):48-58
Servais A, Thomas K, Dello Strologo L, Sayer JA, Bekri S, Bertholet-Thomas A, Bultitude M, Capolongo G, Cerkauskiene R, Daudon M, Doizi S, Gillion V, Gràcia- Garcia S, Halbritter J, Heidet L, van den Heijkant M, Lemoine S, Knebelmann B, Emma F, Levtchenko E
(Siehe online unter https://doi.org/10.1016/j.kint.2020.06.035)
