Mutational analysis of patients with FGF23-related hypophosphatemic rickets

Abstract

Objective: X-linked hypophosphatemic rickets (XLHR) caused by mutations in the PHEX gene is considered to be the most frequent cause of fibroblast growth factor 23 (FGF23)-related congenital hypophosphatemic rickets. In previous studies, mutations in the PHEX gene were detected in 60-70% of patients with clinical diagnoses of XLHR. This leads to the question whether current screening methods for mutations in the PHEX gene are inadequate or whether there is a substantial number of patients with other genetic causes of hypophosphatemic rickets. We conducted a genetic analysis of patients with FGF23-related hypophosphatemic rickets to clarify their etiology and evaluate the prevalence of XLHR among this group. Design and methods: We studied 27 patients with familial and sporadic congenital hypophosphatemic rickets in whom serum FGF23 was above 30 pg/ml using an assay for the full-length protein. Exons and exon-intron junctions of genomic DNA of causative genes for FGF23-related hypophosphatemic rickets were sequenced. PHEX mRNA from peripheral blood was analyzed in some patients. Results: Direct sequencing of genomic DNA identified 11 novel and four known mutations in the PHEX gene. Additionally, there was a large PHEX gene deletion in one case and abnormal PHEX mRNA splicing in another. In summary, 26 patients (96%) had XLHR and one patient had autosomal recessive hypophosphatemic rickets 2. Conclusions: XLHR is by far the most prevalent cause of FGF23-related hypophosphatemic rickets. We propose that analysis of PHEX mRNA from peripheral blood would be appropriate for the first screening step in determining the etiology of FGF23-related hypophosphatemic rickets.

Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets

“…PHEX c.1600C>A (p.P534T) has been reported previously . The novel PHEX c.1600C>T (p.P534S) reported in the current study is at the same codon.…”

Clinical, hormonal, biochemical and genetic characteristics of 75 patients with hypophosphatemic rickets

“…[21] обнаружили дефекты гена PHEX в 79%, Y. Kinoshita и соавт. [22] -в 96% случаев. В нашем исследовании соответствующая величина составила 90,5%.…”

“…[30] обнаружили де-леции экзонов 8-11, а Y. Kinoshita и соавт. [22]-экзо-нов 12-22. В нашем исследовании делеции экзонов составили 10,7%.…”

Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets

“…From previous studies, there are only four mutations in FGF23 that are known to cause ADHR: R176W (50) , R179W (11) , R176Q (13) , and R179Q (51,52) . Gribaa et al (51) stated that any mutations located at an 176 RXXR 179 / S 180 destroy the consensus of cleavage site of FGF23 , thus interrupting its degradation as the cleavage-resistant protein will remain in active intact form, and eventually exaggerates excretion of phosphate in urine, resulting in hypophosphatemia and low serum 1,25(OH) 2 D. Table 2 shows the compilation of reported FGF23 mutations.…”