A novel c.2179T>C mutation blocked the intracellular transport of PHEX protein and caused X-linked hypophosphatemic rickets in a Chinese family.

Molecular Genetics & Genomic Medicine
Baowei LiPeifeng Li

Abstract

X-linked hypophosphatemic rickets (XLH) is a heterogeneous genetic phosphate wasting disorder that occupies the majority of inheritable hypophosphatemic rickets (HR). XLH is caused by loss-of-function mutations in the phosphate-regulating endopeptidase gene (PHEX) located on the X chromosome. In this study, we performed whole-exome sequencing (WES) on the proband to identify the causative gene. The mutations were analyzed by predictive online software, such as PolyPhen-2. Plasmids containing the wild-type (WT) and mutant cDNA of the candidate gene were transfected into HEK293, then, the expression, cellular localization, and glycosylation state of the candidate proteins were detected by western blot, immunostaining, and endoglycosidase H digestion. The expression and concentration of related factor were measured by RT-PCR and ELISA. We identified a novel missense mutation c.2179T>C in the PHEX that results in the substitution of p.Phe727Leu (F727L). This mutation was predicted to be disease-causing by all four predictive online software. In vitro studies demonstrated that the F727L substitution hindered the intracellular trafficking of the mutant PHEX, with ~59% of mutant PHEX protein retained in the endoplasmic reticulum (ER) ...Continue Reading

References

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Methods Mentioned

BETA
glycosylation
PCR
transfection
transfections
ELISA
immunoprecipitation assay
Protein
Precipitation
electrophoresis
X‐ray

Software Mentioned

MODEL
ClustalW
Poly Phen ‐ 2
Burrows Wheeler Aligner ( BWA )
PROVEAN
PolyPhen
Primer Premier
SWISS
Mutation Taster
ANNOVAR

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