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SLC34A3
solute carrier family 34 member 3
SLC34A3 is located on the long (q) arm of chromosome 9, at band 9q34.3. Arm ratio per GRCh38 - banding schematic.
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Overview
SLC34A3 encodes a sodium-dependent phosphate cotransporter expressed predominantly in the proximal tubule of the kidney. This protein plays a central role in maintaining phosphate homeostasis by mediating the reabsorption of inorganic phosphate from the glomerular filtrate back into the bloodstream. The gene is located on chromosome 9 and produces a protein that works alongside other members of the solute carrier 34 family to regulate mineral balance.
When both copies of SLC34A3 carry pathogenic variants, affected individuals typically develop hereditary hypophosphataemic rickets with hypercalciuria, a condition characterised by excessive urinary phosphate loss, low blood phosphate levels, and impaired bone development. Because the condition is autosomal recessive, carriers of a single variant generally do not experience symptoms but can pass the variant to their children.
What the gene does
The SLC34A3 protein functions as a type IIc sodium-phosphate cotransporter, facilitating the movement of inorganic phosphate across the apical membrane of renal proximal tubule cells. This transporter couples the movement of sodium ions down their electrochemical gradient to the uptake of phosphate, enabling the kidney to reclaim filtered phosphate and prevent its loss in urine. Proper phosphate reabsorption is essential for skeletal mineralisation, cellular energy metabolism, and intracellular signalling.
The protein also participates in regulating vitamin D metabolism. When phosphate reabsorption is impaired due to loss of SLC34A3 function, the kidney responds by increasing production of active vitamin D, which in turn enhances intestinal calcium absorption. This compensatory mechanism can lead to elevated urinary calcium excretion and an increased risk of kidney stone formation. The coordinated activity of SLC34A3 with hormonal regulators such as fibroblast growth factor 23 and parathyroid hormone ensures that phosphate levels remain within a narrow physiological range necessary for normal growth and development.
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Chromosome location
SLC34A3 is located on the long arm of chromosome 9 at position 9q34.3. This chromosomal region is near the telomere of chromosome 9. The gene spans multiple exons that together encode a 599-amino-acid protein. Genetic variation in this region can affect transporter expression or function, with consequences for renal phosphate handling.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The SLC34A3 transporter is predicted to contain multiple transmembrane segments that span the cell membrane, forming a channel through which phosphate and sodium ions can pass. The topology and arrangement of these segments are thought to create the structural basis for substrate binding and ion coupling, though detailed structural studies have not been published. Post-translational modifications and interactions with regulatory proteins likely influence transporter trafficking to the cell surface and its activity in the proximal tubule.
Key variants
Pathogenic variants in SLC34A3 are distributed throughout the gene and include missense, nonsense, frameshift, and splice-site changes. Most disease-causing variants disrupt the protein's ability to transport phosphate effectively, either by altering the substrate-binding site, impairing membrane insertion, or destabilising the protein structure. The severity of phosphate wasting can vary depending on the specific combination of variants inherited, with some genotypes associated with more pronounced hypercalciuria or earlier onset of rickets.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in SLC34A3 cause hereditary hypophosphataemic rickets with hypercalciuria, a disorder characterised by low blood phosphate, elevated urinary phosphate excretion, and increased urinary calcium. Affected individuals typically present in childhood with bone pain, skeletal deformities such as bowing of the legs, short stature, and dental abnormalities. The elevated urinary calcium predisposes to nephrocalcinosis and kidney stones. Unlike other forms of hypophosphataemic rickets, this condition is associated with elevated rather than suppressed vitamin D levels. Early diagnosis and phosphate supplementation can improve bone outcomes, though management of hypercalciuria remains challenging.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SLC34A3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SLC34A3 appears on multiple NHS Genomic Medicine Service gene panels. It is listed as a green gene on the Hypophosphataemia or rickets panel (R154), the Nephrocalcinosis or nephrolithiasis panel (R256), and the Skeletal dysplasia panel (R104). Green classification indicates strong evidence supporting the gene-disease association, and testing may be offered through NHS pathways when clinical features suggest an inherited phosphate-wasting disorder or recurrent kidney stones in the context of a family history consistent with autosomal recessive inheritance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of an SLC34A3 variant?
Carriers have one pathogenic variant and one working copy of the gene. Carriers typically do not have symptoms of hypophosphataemic rickets, as the single functional copy provides sufficient phosphate transport. If two carriers have children together, each child has a 25% chance of inheriting both variants and developing the condition.
How is hereditary hypophosphataemic rickets with hypercalciuria diagnosed?
Diagnosis is based on laboratory findings of low serum phosphate, elevated urinary phosphate and calcium excretion, and elevated vitamin D levels, combined with clinical features such as rickets or bone pain. Genetic testing of SLC34A3 confirms the diagnosis and distinguishes this condition from other forms of rickets.
Can SLC34A3-related conditions be treated?
Treatment typically involves oral phosphate supplementation to correct low blood phosphate levels and support bone mineralisation. Monitoring of urinary calcium is important, as excessive supplementation or vitamin D therapy can worsen hypercalciuria and increase the risk of kidney stones. Management is tailored by a specialist metabolic or renal physician.