The PHEX deletion variant (p.Thr605MetfsTer14) causes X-linked hypophosphatemic rickets by reducing protein expression and promoting mineralization.

BACKGROUND: X-linked hypophosphatemic rickets (XLH, OMIM: 307800) is the most prevalent hereditary ricket characterized by hypophosphatemia, rickets, and osteomalacia. XLH resulted from pathogenic variants in PHEX gene. Patients with XLH may experience symptoms that begin in childhood and persist into adulthood or even throughout life, significantly impacting their quality of life. Therefore, studying the genetic etiology and pathogenic mechanisms of XLH is fundamental for the prevention, diagnosis, and treatment of the disease. RESULTS: We identified a novel pathogenic variant in PHEX within XLH families: c.1814delC p.Thr605MetfsTer14. This variant has not been previously reported in patients with XLH. In in vitro functional studies, the variant (c.1814delC p.Thr605MetfsTer14) reduced the protein expression and stability of PHEX and altered its localization. Furthermore, the overexpression of wild-type PHEX inhibited mineralization in contrast to the control group. The PHEX variant (p.Thr605MetfsTer14) exhibited a greater capacity to promote mineralization than the wild-type group. CONCLUSIONS: We propose a potential correlation between reduced protein degradation rate and XLH phenotypes. The PHEX variant protein (p.Thr605MetfsTer14) changed the protein structure, induced mislocalization, accelerated protein degradation, and finally caused a decrease in protein expression, which affected mineralization. Our findings provide valuable data on XLH pathogenesis and genotype-phenotype correlations. The expression and mineralization studies of the PHEX variant offer important insights into the pathogenesis of XLH disease.