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

2019 ◽  
Vol 8 (4) ◽  
pp. 500 ◽  
Author(s):  
Ernesto Martín-Núñez ◽  
Javier Donate-Correa ◽  
Caroline Kannengiesser ◽  
David-Paul De Brauwere ◽  
Christine Leroy ◽  
...  

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.

2012 ◽  
Vol 16 (5) ◽  
pp. 443-450 ◽  
Author(s):  
Michael van Husen ◽  
Anja Lehnhardt ◽  
Ann-Katrin Fischer ◽  
Florian Brinkert ◽  
Sebastian Loos ◽  
...  

2012 ◽  
Vol 5 (3) ◽  
pp. 240-243 ◽  
Author(s):  
P.-A. Westerberg ◽  
T. Linde ◽  
D. Vanderschueren ◽  
J. Billen ◽  
I. Jans ◽  
...  

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 4-10 ◽  
Author(s):  
Michiko Hori ◽  
Yuichiro Shimizu ◽  
Seiji Fukumoto

Abstract Fibroblast growth factor 23 (FGF23) was identified in 2000. Since then, FGF23 has been found to physiologically regulate phosphate metabolism and aberrant actions of FGF23 results in several disorders of phosphate and bone metabolism. In addition, FGF23 plays an important role in the development of chronic kidney disease–mineral and bone disorder. However, further investigations are necessary, especially with regard to the regulation of FGF23 expression. In this minireview, we focus on the physiological and pathophysiological significance of FGF23 in phosphate and bone metabolism.


2007 ◽  
Vol 194 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Mohammed S Razzaque ◽  
Beate Lanske

Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23–klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1α-hydroxylase and sodium–phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23–klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23–klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology.


2007 ◽  
Vol 27 (19) ◽  
pp. 6903-6912 ◽  
Author(s):  
Imad Shams ◽  
Edyta Rohmann ◽  
Veraragavan P. Eswarakumar ◽  
Erin D. Lew ◽  
Satoru Yuzawa ◽  
...  

ABSTRACT Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.


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