Skip to Main content Skip to Navigation
Journal articles

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

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [26 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00969325
Contributor : Marc Lombes <>
Submitted on : Wednesday, April 2, 2014 - 1:25:54 PM
Last modification on : Wednesday, September 16, 2020 - 5:42:33 PM
Long-term archiving on: : Monday, April 10, 2017 - 8:41:01 AM

Files

Mutsaers_HAL_Ultimate.pdf
Files produced by the author(s)

Identifiers

Citation

Henricus Mutsaers, Elena Levtchenko, Laetitia Martinerie, Jeanne 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, Endocrine Society, 2014, 99 (7), pp.E1361-E1367. ⟨10.1210/jc.2014-1123⟩. ⟨inserm-00969325⟩

Share

Metrics

Record views

1012

Files downloads

978