Characterization of Novel PHEX Variants in X-linked Hypophosphatemic Rickets and Genotype-PHEX Activity Correlation
Authors' conclusion
Therefore, our findings demonstrated that novel PHEX variants could disrupt protein function via affecting protein synthesis, post-translational modification, cellular trafficking, and catalytic activity. Our study facilitates a better understanding of XLHR pathogenic mechanism and PHEX activity-phenotype correlation, which is of crucial importance for future diagnosis and treatment of XLHR.
Study context
- Population
- New cohort of HR patients; 16 novel PHEX and 5 novel non-PHEX variants detected
- Participants
- 49 HR patients
- Outcome
- Functional effects of novel PHEX variants
Methodological detailsgenetic cohort, functional variant characterization, CRISPR/Cas9 knock-in mouse models
- Genetic cohort
- Functional variant characterization
- CRISPR/Cas9 knock-in mouse models
Main finding
As reported in the abstract
- Missense variants (Q189H, X750R) slightly reduced protein expression without obviously altering protein length or localization
- Truncating variants significantly impaired PHEX synthesis and produced a shorter immature protein in cells
- No evident correlation between mutation types and clinical phenotypes
- Low PHEX activity tended to go with severe hypophosphatemia and high rickets severity score
- Both knock-in mouse models (Phex c.T1349C, c.C426G) showed XLH manifestations; PhexC426G more severe than PhexT1349C
Original publication
Characterization of Novel PHEX Variants in X-linked Hypophosphatemic Rickets and Genotype-PHEX Activity Correlation. J Clin Endocrinol Metab. Published 5 March 2024. doi:10.
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