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

  1. De Brauwere, David-Paul 6
  2. Martín-Núñez, Ernesto 123
  3. Ureña-Torres, Pablo A. 6
  4. Prieto-Morín, Carol 1
  5. Tagua, Víctor G. 1
  6. Kannengiesser, Caroline 5
  7. Oudin, Claire 5
  8. Friedlander, Gérard 6
  9. Donate-Correa, Javier 134
  10. Leroy, Christine 6
  11. Navarro-González, Juan F. 11224
  1. 1 Hospital Universitario Nuestra Señora de Candelaria
    info

    Hospital Universitario Nuestra Señora de Candelaria

    Santa Cruz de Tenerife, España

    ROR https://ror.org/005a3p084

  2. 2 Universidad de La Laguna
    info

    Universidad de La Laguna

    San Cristobal de La Laguna, España

    ROR https://ror.org/01r9z8p25

  3. 3 Sociedad Española de Nefrología
    info

    Sociedad Española de Nefrología

    Santander, España

  4. 4 Instituto de Salud Carlos III
    info

    Instituto de Salud Carlos III

    Madrid, España

    ROR https://ror.org/00ca2c886

  5. 5 Hôpital Bichat-Claude-Bernard
    info

    Hôpital Bichat-Claude-Bernard

    París, Francia

    ROR https://ror.org/03fdnmv92

  6. 6 Paris Descartes University
    info

    Paris Descartes University

    París, Francia

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Revista:
Journal of Clinical Medicine

ISSN: 2077-0383

Año de publicación: 2019

Volumen: 8

Número: 4

Páginas: 500

Tipo: Artículo

DOI: 10.3390/JCM8040500 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Journal of Clinical Medicine

Objetivos de desarrollo sostenible

Resumen

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 fibroblastgrowth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variationin the KL gene might be associated with alterations in phosphate homeostasis resulting inhyperphosphatemia. We performed sequencing for determining KL gene variants in a group ofresistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencingrevealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation causeda frameshift with substitution of isoleucine for phenylalanine and introduction of a prematuretermination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carriertranscripts in peripheral blood mononuclear cells suggesting degradation of these through anonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variantimpaired 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 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 fibroblastgrowth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variationin the KL gene might be associated with alterations in phosphate homeostasis resulting inhyperphosphatemia. We performed sequencing for determining KL gene variants in a group ofresistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencingrevealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation causeda frameshift with substitution of isoleucine for phenylalanine and introduction of a prematuretermination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carriertranscripts in peripheral blood mononuclear cells suggesting degradation of these through anonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variantimpaired 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 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 fibroblastgrowth factor 23 (FGF23), a major phosphaturic hormone. We hypothesized that genetic variationin the KL gene might be associated with alterations in phosphate homeostasis resulting inhyperphosphatemia. We performed sequencing for determining KL gene variants in a group ofresistant hyperphosphatemic dialysis patients. In a 67-year-old female, blood DNA sequencingrevealed a heterozygous deletion of a T at position 1041 (c.1041delT) in exon 2. This variation causeda frameshift with substitution of isoleucine for phenylalanine and introduction of a prematuretermination codon (p.Ile348Phefs*28). cDNA sequencing showed absence of deletion-carriertranscripts in peripheral blood mononuclear cells suggesting degradation of these through anonsense-mediated RNA decay pathway. Experiments in vitro showed that p.Ile348Phefs*28 variantimpaired 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 geneticdeterminants might be associated to clinical resistant hyperphosphatemia.

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