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@ARTICLE{Etges:906390,
      author       = {Etges, Annika and Hellmig, Nicole and Walenda, Gudrun and
                      Haddad, Bassam G. and Machtens, Jan-Philipp and Morosan,
                      Thomas and Rump, Lars Christian and Scholl, Ute I.},
      title        = {{A} {N}ovel {H}omozygous {KLHL}3 {M}utation as a {C}ause of
                      {A}utosomal {R}ecessive {P}seudohypoaldosteronism {T}ype
                      {II} {D}iagnosed {L}ate in {L}ife},
      journal      = {Nephron},
      volume       = {146},
      number       = {4},
      issn         = {1660-8151},
      address      = {Basel},
      publisher    = {Karger},
      reportid     = {FZJ-2022-01412},
      pages        = {418-428},
      year         = {2022},
      note         = {Funding: This study was funded by the Ministerium für
                      Kultur und Wissenschaftder Landes Nordrhein-Westfalen
                      (Rückkehrprogramm),the Stiftung Charité $(BIH_PRO_406),$
                      and the German ResearchFoundation (DFG, SCHO 1386/2-1;
                      project-ID 431984000, CRC1453), all to U.I.S. It was funded
                      by the Deutsche Forschungsgemeinschaft(German Research
                      Foundation) to J.P.M. (MA 7525/2-1, as part of the research
                      unit FOR 5046, project P2) and by a grantfrom the
                      Interdisciplinary Centre for Clinical Research within
                      thefaculty of Medicine at the RWTH Aachen University (IZKF
                      TN1-3/IA532003). The authors gratefully acknowledge the
                      computingtime granted through JARA on the supercomputer
                      JURECA atForschungszentrum Jülich. Funding agencies had no
                      role in thepreparation of the manuscript.},
      abstract     = {Introduction: Pseudohypoaldosteronism type II (PHA II) is a
                      Mendelian disorder, featuring hyperkalemic acidosis and low
                      plasma renin levels, typically associated with hypertension.
                      Mutations in WNK1, WNK4, CUL3, and KLHL3 cause PHA II, with
                      dominant mutations in WNK1, WNK4, and CUL3 and either
                      dominant or recessive mutations in KLHL3. Fourteen families
                      with recessive KLHL3 mutations have been reported, with
                      diagnosis at the age of 3 months to 56 years, typically in
                      individuals with normal kidney function. Methods: We
                      performed clinical and genetic investigations in a patient
                      with hyperkalemic hypertension and used molecular dynamics
                      simulations, heterologous expression in COS7 cells, and
                      Western blotting to investigate the effect of a KLHL3
                      candidate disease mutation on WNK4 protein expression.
                      Results: The patient, a 58-year-old woman from a
                      consanguineous family, showed hypertension, persistent
                      hyperkalemic acidosis associated with severe muscle pain,
                      nephrolithiasis, chronic kidney disease (CKD), and coronary
                      heart disease. Therapy with hydrochlorothiazide corrected
                      hyperkalemia, hypertension, and muscle pain. Genetic
                      analysis revealed a homozygous p.Arg431Trp mutation at a
                      highly conserved KLHL3 position. Simulations suggested
                      reduced stability of the mutant protein, which was confirmed
                      by Western blot. Compared with wild-type KLHL3,
                      cotransfection of p.Arg431Trp KLHL3 led to increased WNK4
                      protein levels, inferred to cause increased NaCl
                      reabsorption via the thiazide-sensitive carrier and PHA II.
                      Conclusions: Even in patients presenting late in life and in
                      the presence of CKD, PHA II should be suspected if renin
                      levels are low and hyperkalemic acidosis and hypertension
                      are inadequate for CKD stage, particularly in the presence
                      of a suspicious family history},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35093948},
      UT           = {WOS:000750626400001},
      doi          = {10.1159/000521626},
      url          = {https://juser.fz-juelich.de/record/906390},
}