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SLC5A5
solute carrier family 5 member 5
SLC5A5 is located on the short (p) arm of chromosome 19, at band 19p13.11. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
SLC5A5 produces the sodium-iodide symporter (NIS), a transporter responsible for moving iodide into cells of the thyroid gland and several other tissues. The thyroid gland uses iodide to synthesise thyroid hormones, which control metabolic rate, support normal growth, and are essential for brain development during infancy and childhood. The efficiency of iodide accumulation in the thyroid depends on NIS being correctly positioned in the membrane of thyroid follicular cells.
Beyond the thyroid, NIS operates in breast tissue during lactation, where it concentrates iodide into milk to supply breastfed infants with this essential element. The symporter is also present in the ovaries, salivary glands, certain stomach cells, tear glands, and the choroid plexus in the brain. Inherited variants in SLC5A5 that impair symporter function can lead to congenital hypothyroidism, a condition characterised by insufficient thyroid hormone production from birth.
What the gene does
The sodium-iodide symporter couples the transport of sodium and iodide across the cell membrane, utilising the sodium gradient maintained by cellular energy expenditure. This co-transport mechanism allows cells to concentrate iodide against its chemical gradient, achieving intracellular iodide levels many times higher than those found in the bloodstream. In thyroid follicular cells, NIS resides in the membrane facing the blood supply, enabling efficient iodide uptake from circulation.
Once iodide enters the follicular cell, it is subsequently transported into the follicular lumen, where it undergoes oxidation and incorporation into thyroglobulin to form thyroid hormones. The entire process depends on functional NIS protein correctly localised to the cell membrane. During lactation, the same transport mechanism operates in mammary epithelial cells, ensuring adequate iodide content in breast milk to meet the needs of the nursing infant. The symporter's activity in other tissues, including salivary glands and the stomach, supports iodide distribution throughout the body, though the physiological significance in these sites remains an area of ongoing investigation.
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Chromosome location
SLC5A5 is located on the short arm of chromosome 19 at position 13.11 (19p13.11). This chromosomal region contains multiple genes involved in diverse cellular functions. The gene spans genomic sequence sufficient to encode a 643 amino acid protein, organised into coding exons that are transcribed and spliced to produce the mature messenger RNA template for protein synthesis.
Protein structure
The sodium-iodide symporter is a 643 amino acid integral membrane protein with multiple transmembrane segments that allow it to span the cell membrane and create a pathway for ion transport. The protein's structure enables simultaneous binding and movement of both sodium and iodide ions across the lipid bilayer. A disordered region extends from amino acids 623 to 643 at the C-terminus, representing the final portion of the protein that lacks a fixed three-dimensional structure. Disordered regions in membrane transporters can play regulatory roles or provide flexibility for protein interactions, though the specific function of this C-terminal segment has not been fully characterised.
Key variants
Pathogenic variants in SLC5A5 have been identified in individuals with congenital hypothyroidism. Approximately half of the reported disease-causing changes involve deletions that remove part of the gene or disrupt the normal process of protein production, resulting in an incomplete or absent symporter. The remaining pathogenic variants typically involve single nucleotide changes that alter individual amino acids, impairing the protein's ability to transport iodide effectively. These alterations may affect membrane localisation, structural stability, or the ion-binding mechanism itself, ultimately preventing adequate iodide accumulation in the thyroid.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Inherited SLC5A5 variants are associated with congenital hypothyroidism, a condition in which thyroid hormone levels are abnormally low from birth. Affected infants may present with feeding difficulties, prolonged jaundice, constipation, poor growth, and delayed developmental milestones if the condition is not identified and treated promptly. Because thyroid hormones are critical for brain development during the first years of life, early diagnosis through newborn screening programmes and prompt treatment with thyroid hormone replacement are essential to prevent intellectual disability. The condition follows an autosomal recessive inheritance pattern, meaning that two pathogenic variants (one inherited from each parent) are required for an individual to be affected.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SLC5A5 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
SLC5A5 appears on the NHS Genomic Medicine Service PanelApp under the Congenital hypothyroidism panel with green (high evidence) classification (version R145), reflecting its established role in thyroid hormone synthesis disorders. The gene is also included in the Developmental Disorders Genotype-to-Phenotype (DDG2P) resource with green classification, supporting its use in diagnostic genomic testing for relevant clinical presentations within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for SLC5A5-related conditions?
SLC5A5-related congenital hypothyroidism follows an autosomal recessive pattern. This means an individual must inherit two pathogenic variants, one from each parent, to be affected. Carriers with a single pathogenic variant typically have normal thyroid function.
How does the sodium-iodide symporter concentrate iodide in the thyroid?
The symporter uses the sodium gradient across the cell membrane to drive iodide transport against its concentration gradient. By coupling sodium and iodide movement, the protein can accumulate iodide inside thyroid cells at levels much higher than in the bloodstream, enabling efficient thyroid hormone production.
Why is SLC5A5 function important during breastfeeding?
During lactation, the sodium-iodide symporter transports iodide into breast milk, providing nursing infants with the iodide needed to produce their own thyroid hormones. This ensures adequate thyroid hormone levels during a critical period of brain development in early life.