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

Front Genet. 2022 Feb 17;13:792183. doi: 10.3389/fgene.2022.792183. eCollection 2022.

PMID: 35251124

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

Highlights: This study's genetic and functional investigations revealed a novel genetic cause of XLH: the heterozygous mutation of PHEX (NM 000444.5: c.1768G > A).

Abstract

Background: 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.

Methods and results: A novel heterozygous mutation of PHEX (NM_000444.5: c.1768G > A) was identified 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.

Conclusion: 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.

Keywords: X-linked hypophosphatamia (XLH), functional experiments, gene mutations, phosphate-regulating endopeptidase homolog X-linked gene (PHEX), whole-exome sequencing (WES)