Identification of a Novel Missense Mutation of the PHEX Gene in a Large Chinese Family with X-Linked Hypophosphataemia

Yanting Yang,Mohan Liu,Hongqian Liu,Yuanda Wang,Ying Shen,Xiaodong Wang,Siyu Dai

doi:10.3389/fgene.2022.792183

Abstract

X-linked hypophosphataemia (XLH) is an X-linked dominant rare disease that refers to the most common hereditary hypophosphatemia (HH) caused by mutations in the phosphate-regulating endopeptidase homolog X-linked gene (PHEX; OMIM: * 300550). However, mutations that have already been reported cannot account for all cases of XLH. Extensive genetic analysis can thus be helpful for arriving at the diagnosis of XLH. Herein, we identified a novel heterozygous mutation of PHEX (NM_000444.5: c.1768G > A) in a large Chinese family with XLH by whole-exome sequencing (WES). In addition, the negative effect of this mutation in PHEX was confirmed by both bioinformatics analysis and in vitro experimentation. The three-dimensional protein-model analysis predicted that this mutation might impair normal zinc binding. Immunofluorescence staining, qPCR, and western blotting analysis confirmed that the mutation we detected attenuated PHEX protein expression. The heterozygous mutation of PHEX (NM_000444.5: c.1768G > A) identified in this study by genetic and functional experiments constitutes a novel genetic cause of XLH, but further study will be required to expand its use in clinical and molecular diagnoses of XLH.

Highlights

Hereditary hypophosphataemia (HH) is a type of congenital disease of the phosphate-regulating homeostatic system, including phosphate-metabolism disorder and decreased renal tubular phosphate reabsorption
X-linked hypophosphataemia (XLH) is an X-linked dominant monogenic rare disease caused by mutations in the phosphate-regulating endopeptidase homolog X-linked gene (PHEX; OMIM:* 300550), with an incidence of 3.9/100,000 live births and a prevalence ranging from 1.7/100,000 children to 4.8/100,000 individuals (Beck-Nielsen et al, 2009; Endo et al, 2015; Rafaelsen et al, 2016)
The proband’s elder sister (IV-3) who achieved a height of 137 cm showed the aforementioned signs and bore a boy (V-2) who shows no signs of rickets or osteomalacia

Summary

Introduction

Hereditary hypophosphataemia (HH) is a type of congenital disease of the phosphate-regulating homeostatic system, including phosphate-metabolism disorder and decreased renal tubular phosphate reabsorption. HR can be classified as FGF23-associated and non-associated, and HR is subdivided into several forms, including X-linked hypophosphataemia (XLH), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemia (ARHR), and hereditary hypophosphataemic rickets with hypercalciuria (HHRH). X-linked hypophosphataemia (XLH) is considered the most common form of FGF23-related, inherited HR. Novel PHEX Mutation Causing XLH (Marcucci and Brandi, 2021; Quarles, 2012). XLH is an X-linked dominant monogenic rare disease caused by mutations in the phosphate-regulating endopeptidase homolog X-linked gene (PHEX; OMIM:* 300550), with an incidence of 3.9/100,000 live births and a prevalence ranging from 1.7/100,000 children to 4.8/100,000 individuals (children and adults) (Beck-Nielsen et al, 2009; Endo et al, 2015; Rafaelsen et al, 2016). The representative features of this disease are hypophosphataemia, diminished synthesis of active vitamin D (1,25 [OH]2 vitamin D), rickets, osteomalacia, odontomalacia, and disproportionately short stature (Haffner et al, 2019)

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