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A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway

Hyperphosphatemia is commonly present in end-stage renal disease. Klotho (KL) is implicated in phosphate homeostasis since it acts as obligate co-receptor for the fibroblast growth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variation in the KL gene might be associa...

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Autores principales: Martín-Núñez, Ernesto, Donate-Correa, Javier, Kannengiesser, Caroline, De Brauwere, David-Paul, Leroy, Christine, Oudin, Claire, Friedlander, Gérard, Prieto-Morín, Carol, Tagua, Víctor G., Ureña-Torres, Pablo A., Navarro-González, Juan F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517886/
https://www.ncbi.nlm.nih.gov/pubmed/31013726
http://dx.doi.org/10.3390/jcm8040500
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author Martín-Núñez, Ernesto
Donate-Correa, Javier
Kannengiesser, Caroline
De Brauwere, David-Paul
Leroy, Christine
Oudin, Claire
Friedlander, Gérard
Prieto-Morín, Carol
Tagua, Víctor G.
Ureña-Torres, Pablo A.
Navarro-González, Juan F.
author_facet Martín-Núñez, Ernesto
Donate-Correa, Javier
Kannengiesser, Caroline
De Brauwere, David-Paul
Leroy, Christine
Oudin, Claire
Friedlander, Gérard
Prieto-Morín, Carol
Tagua, Víctor G.
Ureña-Torres, Pablo A.
Navarro-González, Juan F.
author_sort Martín-Núñez, Ernesto
collection PubMed
description Hyperphosphatemia is commonly present in end-stage renal disease. Klotho (KL) is implicated in phosphate homeostasis since it acts as obligate co-receptor for the fibroblast growth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variation in the KL gene might be associated with alterations in phosphate homeostasis resulting in hyperphosphatemia. We performed sequencing for determining KL gene variants in a group of resistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencing revealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation caused a frameshift with substitution of isoleucine for phenylalanine and introduction of a premature termination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carrier transcripts in peripheral blood mononuclear cells suggesting degradation of these through a nonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variant impaired FGF23 signaling pathway, indicating a functional inactivation of the gene. In the patient, serum levels of KL were 2.9-fold lower than the mean level of a group of matched dialysis subjects, suggesting a compromise in the circulating protein concentration due to haploinsufficiency. These findings provide a new loss-of-function variant in the human KL gene, suggesting that genetic determinants might be associated to clinical resistant hyperphosphatemia.
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spelling pubmed-65178862019-05-31 A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway Martín-Núñez, Ernesto Donate-Correa, Javier Kannengiesser, Caroline De Brauwere, David-Paul Leroy, Christine Oudin, Claire Friedlander, Gérard Prieto-Morín, Carol Tagua, Víctor G. Ureña-Torres, Pablo A. Navarro-González, Juan F. J Clin Med Article Hyperphosphatemia is commonly present in end-stage renal disease. Klotho (KL) is implicated in phosphate homeostasis since it acts as obligate co-receptor for the fibroblast growth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variation in the KL gene might be associated with alterations in phosphate homeostasis resulting in hyperphosphatemia. We performed sequencing for determining KL gene variants in a group of resistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencing revealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation caused a frameshift with substitution of isoleucine for phenylalanine and introduction of a premature termination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carrier transcripts in peripheral blood mononuclear cells suggesting degradation of these through a nonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variant impaired FGF23 signaling pathway, indicating a functional inactivation of the gene. In the patient, serum levels of KL were 2.9-fold lower than the mean level of a group of matched dialysis subjects, suggesting a compromise in the circulating protein concentration due to haploinsufficiency. These findings provide a new loss-of-function variant in the human KL gene, suggesting that genetic determinants might be associated to clinical resistant hyperphosphatemia. MDPI 2019-04-12 /pmc/articles/PMC6517886/ /pubmed/31013726 http://dx.doi.org/10.3390/jcm8040500 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Martín-Núñez, Ernesto
Donate-Correa, Javier
Kannengiesser, Caroline
De Brauwere, David-Paul
Leroy, Christine
Oudin, Claire
Friedlander, Gérard
Prieto-Morín, Carol
Tagua, Víctor G.
Ureña-Torres, Pablo A.
Navarro-González, Juan F.
A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title_full A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title_fullStr A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title_full_unstemmed A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title_short A Novel Heterozygous Deletion Variant in KLOTHO Gene Leading to Haploinsufficiency and Impairment of Fibroblast Growth Factor 23 Signaling Pathway
title_sort novel heterozygous deletion variant in klotho gene leading to haploinsufficiency and impairment of fibroblast growth factor 23 signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517886/
https://www.ncbi.nlm.nih.gov/pubmed/31013726
http://dx.doi.org/10.3390/jcm8040500
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