FGF-23 (fibroblast growth factor-23) is a phosphatonin secreted by osteocytes. In X-linked hypophosphatemia (XLH), which mutation leads to FGF-23 excess and what is the biochemical consequence?
- A Gain-of-function mutation in FGFR1 → constitutive FGF-23 receptor activation → renal phosphate wasting independent of FGF-23 ligand levels
- B Loss-of-function mutation in PHEX (phosphate-regulating endopeptidase homolog X-linked) → impaired FGF-23 degradation → FGF-23 excess → reduced NaPi-IIa/IIc cotransporters in renal proximal tubule → phosphaturia and low serum phosphate ✓
- C Loss-of-function mutation in klotho co-receptor → inability to signal FGF-23 to suppress phosphate reabsorption, causing hypophosphatemia
- D Mutation in CYP27B1 (1-alpha hydroxylase) → impaired calcitriol synthesis → secondary hyperparathyroidism → FGF-23 elevation
Correct answer: B. Loss-of-function mutation in PHEX (phosphate-regulating endopeptidase homolog X-linked) → impaired FGF-23 degradation → FGF-23 excess → reduced NaPi-IIa/IIc cotransporters in renal proximal tubule → phosphaturia and low serum phosphate
Explanation
X-linked hypophosphatemia is caused by loss-of-function mutations in PHEX, a zinc metalloprotease endopeptidase. PHEX normally degrades FGF-23. Without PHEX activity, FGF-23 accumulates and acts on renal proximal tubule cells to downregulate NaPi-IIa and NaPi-IIc sodium-phosphate cotransporters, causing phosphaturia and hypophosphatemia. FGF-23 also suppresses 1-alpha hydroxylase (CYP27B1), so calcitriol is inappropriately low for the hypophosphatemia, impairing gut phosphate absorption further and causing rickets/osteomalacia.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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