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Identification of a p.Trp403* nonsense variant in PHEX causing X‐linked hypophosphatemia by inhibiting p38 MAPK signaling

Wei Li,Lingfang Tan,Xin Li,Xiaoyu Zhang,Xiaoyan Wu,Hongbo Chen,Li-hua Hu,Xiaobei Wang,Xiaoping Luo,Fan Wang,Chengqi Xu,Qiuyun Chen,R. Jin,Q. Wang

Published 2019 in Human Mutation

ABSTRACT

X‐linked hypophosphatemia (XLH) is the most common hereditary rickets, caused by mutations in PHEX encoding the phosphate regulating endopeptidase homolog X‐linked. Here, we report a nonsense variant in exon 11 of PHEX (c.1209G>A p.Trp403*) cosegregating with XLH in a Chinese family with a LOD score of 2.70. Real‐time reverse transcription polymerase chain reaction analysis demonstrated that p.Trp403* variant did not cause nonsense‐mediated mRNA decay (NMD), but significantly increased the expression level of FGF23 mRNA in the patients. Interestingly, p.Trp403* significantly reduced phosphorylation of p38 mitogen‐activated protein kinase (MAPK) but not ERK1/2. Moreover, overexpression of FGF23 significantly decreased phosphorylation of p38 MAPK, whereas knockdown of FGF23 by siRNA significantly increased phosphorylation of p38 MAPK. These data suggest that p.Trp403* may not function via an NMD mechanism, and instead causes XLH via a novel signaling mechanism involving PHEX, FGF23, and p38 MAPK. This finding provides important insights into genetic and molecular mechanisms for the pathogenesis of XLH.

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