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Kidney Week

Abstract: TH-PO730

Genetic and Functional Characterization of PHEX Gene Variants in 42 Children with X-Linked Hypophosphatemic Rickets

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Zhang, Aihua, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Zheng, Bixia, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Wang, Chunli, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Zhang, Yue, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Ding, Guixia, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Huang, Songming, Children's Hospital of Nanjing Medical University, Nanjing, China
  • Jia, Zhanjun, Children's Hospital of Nanjing Medical University, Nanjing, China
Background

X-linked hypophosphatemia, a disorder of renal phosphate wasting and the most common heritable form of rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog (PHEX). The aim of this study was to explore the molecular basis of 42 children with HR in the Chinese population.

Methods

All patients were analyzed for the PHEX gene by direct sequencing. When no mutations were detected in PHEX gene, multiplex ligation-dependent probe amplification (MLPA) analysis was performed. PHEX non-truncating mutation and two truncated mutations were characterized in vitro by assessing their effects on PHEX expression, subcellular localization and glycosylation pattern.

Results

Among 42 patients, 40 patients (95%) harbored mutations in the PHEX gene. In particular, we detected 35 different mutations, including eleven indel mutations including nine frameshift mutations resulting from small deletions or insertions and one 3bp deletion mutation (31.4%), seven missense (20%), seven splice sites mutations(20%), five nonsense (14.2%), and five exonic deletion (14.2%). Among these mutations, 21 mutations have not been previously described in the literature or entered in PHEXdb and HGMD. Clinical presentation and disease severity did not show an evident correlation between the truncating and non-truncating mutation type. Like the nonsense mutaion R567X and Q714X, five of the six non-truncating mutation detected in our cohort also led to retention of the PHEX protein in endoplasmic reticulum, in an immature form, as determined by glycosylation pattern and proteasomal degradation analysis and immunofluorescence.

Conclusion

Our findings expand the mutation spectrum of PHEX, confirm that mutations in PHEX are the most frequent cause of HR, and truncating mutations is the most often mutation type in Chinese patients. Our clinical and experimental evidence also showed no correlation between the degree of disease severity and the PHEX genotypes.