Switch in FGFR 3 and 4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions. - Archive ouverte HAL Access content directly
Journal Articles Journal of Clinical Endocrinology and Metabolism Year : 2014

Switch in FGFR 3 and 4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.

(1, 2) , (3) , (1) , (4) , (3) , (5) , (4) , (6) , (1, 7)
1
2
3
4
5
6
7

Abstract

: Context: Sotos syndrome is a rare genetic disorder with a distinct phenotypic spectrum including overgrowth and learning difficulties. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. Objective: We strived to elucidate the evanescent nature of the observed hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4 - which are both associated with FGF23-mediated mineral homeostasis - in the developing human kidney. Design: RT-qPCR and immunohistochemical analyses were used on archival human kidney samples to investigate expression of the FGFR signaling pathway during renal development. Results: We demonstrated that renal gene and protein expression of both FGFRs increased during fetal development between the gestational ages (GA) of 14-40 weeks. Yet, FGFR4 expression increased more rapidly as compared to FGFR3 (slope: 0.047 vs. 0.0075, p = 0.0018). Moreover, gene and protein expression of the essential FGFR co-receptor, Klotho, also increased with a significant positive correlation between FGFR and Klotho mRNA expression during renal development. Interestingly, we found that perinatal FGFR4 expression (GA 38-40 weeks) was 7-fold higher as compared to FGFR3 (p=0.0035), while in adult kidney tissues, FGFR4 gene expression level was more than 2-fold lower compared to FGFR3 (p=0.0029), thus identifying a molecular developmental switch of FGFR isoforms. Conclusion: We propose that the heterozygous FGFR4 deletion, as observed in the Sotos syndrome patient, leads to a compromised FGF23 signaling during infancy accounting for transient hypercalcemia. These findings represent a novel and intriguing view on FGF23-mediated calcium homeostasis.
Fichier principal
Vignette du fichier
Mutsaers_HAL_Ultimate.pdf (361 Ko) Télécharger le fichier
Vignette du fichier
Fig_Mustaers.pdf (54.09 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Origin : Files produced by the author(s)
Loading...

Dates and versions

inserm-00969325 , version 1 (02-04-2014)

Identifiers

Cite

Henricus A.M Mutsaers, Elena N. Levtchenko, Laetitia Martinerie, Jeanne Clm Pertijs, Karel Allegaert, et al.. Switch in FGFR 3 and 4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.: Ontogeny of FGFR 3 and 4 in human kidney. Journal of Clinical Endocrinology and Metabolism, 2014, 99 (7), pp.E1361-E1367. ⟨10.1210/jc.2014-1123⟩. ⟨inserm-00969325⟩
365 View
119 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More