High-throughput mutation analysis for known and novel single-gene causes of kidney stones and related disorders

• Applicant: Professor Dr. Jan Halbritter
• Subject Area: Nephrology ; Human Genetics ; Reproductive Medicine, Urology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 291110008

• Final Report Year: 2021

Final Report Abstract

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.

Publications

• Kidney Int. 2018 Jan;93(1):204-213
  Daga, Ankana; Majmundar, Amar J.; Braun, Daniela A.; Gee, Heon Yung; Lawson, Jennifer A.; Shril, Shirlee; Jobst-Schwan, Tilman; Vivante, Asaf; Schapiro, David; Tan, Weizhen; Warejko, Jillian K.; Widmeier, Eugen; Nelson, Caleb P.; Fathy, Hanan M.; Gucev, Zoran; Soliman, Neveen A.; Hashmi, Seema; Halbritter, Jan; Halty, Margarita; ... & Hildebrandt, Friedhelm
  
• Update on Hereditary Kidney Stone Disease and Introduction of a New Clinical Patient Registry in Germany. Front Pediatr. 2018 Mar 7;6:47
  Halbritter, Jan; Seidel, Anna; Müller, Luise; Schönauer, Ria & Hoppe, Bernd
  
• Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting. Urolithiasis. 2019 Feb 23
  Schönauer, Ria; Petzold, Friederike; Lucinescu, Wilhelmina; Seidel, Anna; Müller, Luise; Neuber, Steffen; Bergmann, Carsten; Sayer, John A.; Werner, Andreas & Halbritter, Jan
  
• 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, Ali; Majmundar, Amar J.; Ullah, Ihsan; Afzal, Ayesha; Braun, Daniela A.; Shril, Shirlee; Daga, Ankana; Jobst-Schwan, Tilman; Ahmad, Mumtaz; Sayer, John A.; Gee, Heon Yung; Halbritter, Jan; Knöpfel, Thomas; Hernando, Nati; Werner, Andreas; Wagner, Carsten; Khaliq, Shagufta & Hildebrandt, Friedhelm
  
• 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, Isabel; Münch, Johannes; Wagner, Timo; Schönauer, Ria; Bachmann, Anette; Weimann, Antje; Hentschel, Julia; Lindner, Tom H.; Seehofer, Daniel; Bergmann, Carsten; Jamra, Rami Abou & Halbritter, Jan
  
• 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, Johannes; Kirschner, Karin M; Schlee, Hendrik; Kraus, Cornelia; Schönauer, Ria; Jin, Wenjun; Le Duc, Diana; Scholz, Holger & Halbritter, Jan
  
• Matching Clinical and Genetic Diagnoses in Autosomal Dominant Polycystic Kidney Disease Reveals Novel Phenocopies and Potential Candidate Genes. Genet Med. 2020 May 13
  Schönauer, Ria; Baatz, Sebastian; Nemitz-Kliemchen, Melanie; Frank, Valeska; Petzold, Friederike; Sewerin, Sebastian; Popp, Bernt; Münch, Johannes; Neuber, Steffen; Bergmann, Carsten & Halbritter, Jan
  
• Novel Nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment. Kidney Int. 2020 Jun 4:S0085- 2538(20)30632-3
  Schönauer, Ria; Jin, Wenjun; Ertel, Anastasia; Nemitz-Kliemchen, Melanie; Panitz, Nydia; Hantmann, Elena; Seidel, Anna; Braun, Daniela A.; Shril, Shirlee; Hansen, Matthias; Shahzad, Khurrum; Sandford, Richard; Saunier, Sophie; Benmerah, Alexandre; Bergmann, Carsten; Hildebrandt, Friedhelm & Halbritter, Jan
  
• 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, Aude; Thomas, Kay; Dello Strologo, Luca; Sayer, John A.; Bekri, Soumeya; Bertholet-Thomas, Aurelia; Bultitude, Matthew; Capolongo, Giovanna; Cerkauskiene, Rimante; Daudon, Michel; Doizi, Steeve; Gillion, Valentine; Gràcia-Garcia, Silvia; Halbritter, Jan; Heidet, Laurence; van den Heijkant, Marleen; Lemoine, Sandrine; Knebelmann, Bertrand; Emma, Francesco; ... & Levtchenko, Elena