SLC34A3 – Hereditary Hypophosphatemic Rickets with Hypercalciuria

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by renal phosphate wasting, hypophosphatemia, rickets, elevated 1,25-dihydroxyvitamin D, and hypercalciuria that may manifest with nephrolithiasis or nephrocalcinosis. SLC34A3 (NaPi-IIc) encodes the renal sodium-phosphate cotransporter predominantly expressed in proximal tubular brush borders, crucial for phosphate homeostasis (PMID:16358214).

Genetic evidence for SLC34A3 in HHRH is definitive: biallelic loss-of-function and missense mutations have been identified in over 60 unrelated probands, including a Bedouin kindred with 10 affected individuals and multiple unrelated families (PMID:16358214; PMID:37981601). Inheritance is autosomal recessive, with carriers showing variable hypercalciuria without overt rickets.

Segregation analysis demonstrates segregation of compound heterozygous or homozygous variants with disease in large pedigrees: e.g., ten affected relatives in the consanguineous Bedouin kindred all homozygous for a frameshift in SLC34A3 (PMID:16358214). Heterozygous relatives frequently exhibit hypercalciuria and mild hypophosphatemia, indicating a gene dosage effect.

The variant spectrum includes nonsense, frameshift, splice-site, missense, and intronic deletions. The recurrent European founder allele p.Ser192Leu (c.575C>T (p.Ser192Leu)) accounts for ~53% of probands lacking skeletal involvement, underscoring its diagnostic relevance (PMID:37981601).

Functional assays in Xenopus oocytes and opossum kidney cells reveal that missense mutations (e.g., p.Gly196Arg, p.Arg468Trp) cause endoplasmic reticulum retention, while p.Ser138Phe and p.Arg564Cys reduce Vmax and accelerate degradation, confirming loss-of-function as the pathogenic mechanism (PMID:22159077).

Integration of genetic and functional data yields a ClinGen Definitive gene-disease association. Recognition of SLC34A3-related HHRH enables targeted genetic testing, phosphate supplementation therapy, and avoidance of vitamin D analogs that exacerbate hypercalciuria. Key take-home: biallelic SLC34A3 mutations definitively cause HHRH, guiding precise diagnosis and tailored management.

References

• American Journal of Human Genetics • 2006 • SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis PMID:16358214
• Calcified Tissue International • 2024 • Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review PMID:37981601
• American Journal of Physiology. Cell Physiology • 2012 • Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria PMID:22159077

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