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- Title
Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.
- Authors
Mutsaers, Henricus A M; Levtchenko, Elena N; Martinerie, Laetitia; Pertijs, Jeanne C L M; Allegaert, Karel; Devriendt, Koenraad; Masereeuw, Rosalinde; Monnens, Leo A H; Lombès, Marc
- Abstract
<bold>Context: </bold>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.<bold>Objective: </bold>We strove to elucidate the evanescent nature of the observed hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4, which are both associated with fibroblast growth factor (FGF) 23-mediated mineral homeostasis, in the developing human kidney.<bold>Design: </bold>Quantitative RT-PCR and immunohistochemical analyses were used on archival human kidney samples to investigate the expression of the FGFR signaling pathway during renal development.<bold>Results: </bold>We demonstrated that renal gene and protein expression of both FGFRs increased during fetal development between the gestational ages (GAs) of 14-40 weeks. Yet FGFR4 expression increased more rapidly as compared with FGFR3 (slope 0.047 vs 0.0075, P = .0018). Moreover, gene and protein expression of the essential FGFR coreceptor, 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 wk) was 7-fold higher as compared with FGFR3 (P = .0035), whereas in adult kidney tissues, FGFR4 gene expression level was more than 2-fold lower compared with FGFR3 (P = .0029), thus identifying a molecular developmental switch of FGFR isoforms.<bold>Conclusion: </bold>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.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2014, Vol 99, Issue 7, pE1361
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2014-1123