SLC34A1 – Primary Fanconi Syndrome

SLC34A1 encodes the renal sodium–phosphate cotransporter NaPi-IIa, which mediates proximal tubular phosphate reabsorption. Biallelic loss-of-function variants in SLC34A1 cause autosomal recessive primary Fanconi syndrome, characterized by generalized proximal tubular dysfunction, phosphaturia, aminoaciduria, glycosuria, nephrocalcinosis, and often hypercalciuria and hypercalcemia.

Genetic analyses in three independent cohorts have identified homozygous variants in affected individuals: a recurrent inserted duplication p.Ile154_Val160dup in two unrelated infants and two adult siblings (PMID:29029121), a homozygous missense p.Arg495His in two Argentinean siblings (PMID:25050900), and a novel homozygous p.Arg215Gln in a consanguineous family (PMID:27378183). Segregation of the p.Ile154_Val160dup allele in a multiplex pedigree confirmed co-segregation with disease in two additional affected relatives.

The variant spectrum comprises an in-frame duplicated stretch (p.Ile154_Val160dup) and missense substitutions (p.Arg495His, p.Arg215Gln), all predicted to abolish cotransporter function. In vitro localization assays demonstrate ER retention of mutant NaPi-IIa in an immature, underglycosylated state, while uptake studies reveal markedly reduced phosphate transport in Xenopus oocytes and opossum kidney cells.

Mechanistically, these data establish a loss-of-function effect via impaired trafficking and accelerated proteasomal degradation of NaPi-IIa, consistent with autosomal recessive inheritance. Functional concordance across models underscores haploinsufficiency of NaPi-IIa as the pathogenic mechanism.

Clinically, patients present from infancy to adolescence with generalized proximal tubulopathy, hypophosphatemia, hypercalciuria, nephrocalcinosis, and secondary hypercalcemia. Longitudinal follow-up highlights the utility of genetic diagnosis for early intervention and management of mineral and bone disorders.

Integration of genetic and experimental evidence yields a Strong gene–disease association. SLC34A1 testing should be incorporated into diagnostic workflows for unexplained primary Fanconi syndrome, guiding appropriate phosphate supplementation and monitoring strategies. Key Take-home: Biallelic SLC34A1 loss-of-function variants reliably cause primary Fanconi syndrome, informing genetic diagnosis and clinical care.

References

• The Journal of clinical endocrinology and metabolism • 2017 • Clinical Heterogeneity and Phenotypic Expansion of NaPi-IIa-Associated Disease PMID:29029121
• The Journal of clinical endocrinology and metabolism • 2014 • Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis PMID:25050900
• Pediatric nephrology (Berlin, Germany) • 2016 • Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency PMID:27378183

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