Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone

A. J. Bleyer, M. Živná, H. Hulková, K. Hodanová, P. Vyletal, J. Sikora, J. Živný, J. Sovová, T. C. Hart, J. N. Adams, M. Elleder, K. Kapp, R. Haws, L. D. Cornell, S. Kmoch, P. S. Hart

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. Methods: Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. Results: The mutation affects endoplasmic reticulum co-translational translocation and post-translational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. Conclusions: A novel REN genemutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.

Original languageEnglish (US)
Pages (from-to)411-422
Number of pages12
JournalClinical Nephrology
Volume74
Issue number6
StatePublished - Dec 2010

Fingerprint

Fludrocortisone
Dominant Genes
Renin
Polyuria
Hyperuricemia
Anemia
Chronic Renal Insufficiency
Mutation
Protein Sorting Signals
Kidney
Aptitude
Kidney Diseases
Amino Acid Substitution
Therapeutics
Glomerular Filtration Rate
Endoplasmic Reticulum
Cysteine
Arginine
Amino Acid Sequence
Cytoplasm

Keywords

  • Anemia
  • Children
  • Fludrocortisone
  • Hyperuricemia
  • Renin mutation

ASJC Scopus subject areas

  • Nephrology

Cite this

Bleyer, A. J., Živná, M., Hulková, H., Hodanová, K., Vyletal, P., Sikora, J., ... Hart, P. S. (2010). Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. Clinical Nephrology, 74(6), 411-422.

Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. / Bleyer, A. J.; Živná, M.; Hulková, H.; Hodanová, K.; Vyletal, P.; Sikora, J.; Živný, J.; Sovová, J.; Hart, T. C.; Adams, J. N.; Elleder, M.; Kapp, K.; Haws, R.; Cornell, L. D.; Kmoch, S.; Hart, P. S.

In: Clinical Nephrology, Vol. 74, No. 6, 12.2010, p. 411-422.

Research output: Contribution to journalArticle

Bleyer, AJ, Živná, M, Hulková, H, Hodanová, K, Vyletal, P, Sikora, J, Živný, J, Sovová, J, Hart, TC, Adams, JN, Elleder, M, Kapp, K, Haws, R, Cornell, LD, Kmoch, S & Hart, PS 2010, 'Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone', Clinical Nephrology, vol. 74, no. 6, pp. 411-422.
Bleyer, A. J. ; Živná, M. ; Hulková, H. ; Hodanová, K. ; Vyletal, P. ; Sikora, J. ; Živný, J. ; Sovová, J. ; Hart, T. C. ; Adams, J. N. ; Elleder, M. ; Kapp, K. ; Haws, R. ; Cornell, L. D. ; Kmoch, S. ; Hart, P. S. / Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. In: Clinical Nephrology. 2010 ; Vol. 74, No. 6. pp. 411-422.
@article{ebc9eefbe95a4575b83d638d2b55f5e0,
title = "Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone",
abstract = "Background: A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. Methods: Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. Results: The mutation affects endoplasmic reticulum co-translational translocation and post-translational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. Conclusions: A novel REN genemutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.",
keywords = "Anemia, Children, Fludrocortisone, Hyperuricemia, Renin mutation",
author = "Bleyer, {A. J.} and M. Živn{\'a} and H. Hulkov{\'a} and K. Hodanov{\'a} and P. Vyletal and J. Sikora and J. Živn{\'y} and J. Sovov{\'a} and Hart, {T. C.} and Adams, {J. N.} and M. Elleder and K. Kapp and R. Haws and Cornell, {L. D.} and S. Kmoch and Hart, {P. S.}",
year = "2010",
month = "12",
language = "English (US)",
volume = "74",
pages = "411--422",
journal = "Clinical Nephrology",
issn = "0301-0430",
publisher = "Dustri-Verlag Dr. Karl Feistle",
number = "6",

}

TY - JOUR

T1 - Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone

AU - Bleyer, A. J.

AU - Živná, M.

AU - Hulková, H.

AU - Hodanová, K.

AU - Vyletal, P.

AU - Sikora, J.

AU - Živný, J.

AU - Sovová, J.

AU - Hart, T. C.

AU - Adams, J. N.

AU - Elleder, M.

AU - Kapp, K.

AU - Haws, R.

AU - Cornell, L. D.

AU - Kmoch, S.

AU - Hart, P. S.

PY - 2010/12

Y1 - 2010/12

N2 - Background: A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. Methods: Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. Results: The mutation affects endoplasmic reticulum co-translational translocation and post-translational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. Conclusions: A novel REN genemutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.

AB - Background: A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. Methods: Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. Results: The mutation affects endoplasmic reticulum co-translational translocation and post-translational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. Conclusions: A novel REN genemutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.

KW - Anemia

KW - Children

KW - Fludrocortisone

KW - Hyperuricemia

KW - Renin mutation

UR - http://www.scopus.com/inward/record.url?scp=78649857332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649857332&partnerID=8YFLogxK

M3 - Article

VL - 74

SP - 411

EP - 422

JO - Clinical Nephrology

JF - Clinical Nephrology

SN - 0301-0430

IS - 6

ER -