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TRPM6
transient receptor potential cation channel subfamily M member 6
TRPM6 is located on the long (q) arm of chromosome 9, at band 9q21.13. Arm ratio per GRCh38 - banding schematic.
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Overview
TRPM6 encodes a member of the transient receptor potential (TRP) channel family, which forms ion channels in cell membranes. This particular channel primarily transports magnesium ions across epithelial cell membranes, whilst also permitting small amounts of calcium to pass through. The protein plays a critical role in whole-body magnesium homeostasis by controlling absorption in the intestine and reabsorption in the kidney.
Magnesium serves as a cofactor for over 300 enzymatic reactions, supporting energy production, DNA and protein synthesis, and cellular signalling. When TRPM6 function is impaired, the body cannot maintain adequate magnesium levels, resulting in a cascade of metabolic and neurological disturbances. Because pathogenic variants in TRPM6 are inherited in an autosomal recessive pattern, both gene copies must carry a mutation for disease to manifest.
What the gene does
The TRPM6 protein functions as a highly selective magnesium channel embedded in the plasma membrane of epithelial cells. These cells line the distal convoluted tubules of the kidney and the large intestine, positioning the channel at key sites for magnesium regulation. When magnesium levels fall below physiological thresholds, TRPM6 channels open to permit absorption from dietary sources in the gut and reabsorption from the renal filtrate, preventing urinary loss.
Conversely, when magnesium concentrations are sufficient or elevated, the channel restricts uptake and allows excess magnesium to be excreted in urine. This dual regulatory mechanism ensures tight control of serum magnesium within a narrow physiological range. The protein also contributes to calcium homeostasis, though to a lesser extent than its effect on magnesium. Magnesium itself is essential for the synthesis of parathyroid hormone, which further regulates calcium levels, creating an interconnected mineral regulatory network.
Beyond ion transport, magnesium supports the normal function of motor neurones that control muscle contraction. Deficiency in this mineral impairs neuromuscular signalling, manifesting as spasms, tremor, and seizures.
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Chromosome location
TRPM6 is located on the long arm of chromosome 9 at band 9q21.13. The genomic region spans multiple exons encoding a large transcript that produces a 2,022-amino-acid protein. This chromosomal location is relatively stable, with no common structural variants reported in the general population.
Protein structure
The TRPM6 protein comprises 2,022 amino acids and exhibits a modular architecture typical of TRP channel family members. The C-terminal region contains an alpha-type protein kinase domain spanning amino acids 1,750 to 1,980, which is thought to regulate channel activity through phosphorylation events. Two disordered regions are present: one extending from amino acids 1,479 to 1,516, and another at the very C-terminus from amino acids 1,997 to 2,022. Disordered regions often serve as flexible linkers or sites for protein-protein interactions, contributing to the channel's responsiveness to cellular signals and regulatory molecules.
Key variants
Pathogenic variants in TRPM6 typically result in loss of functional channel protein, either through premature truncation, mis-folding, or defective trafficking to the cell membrane. At least 38 distinct mutations have been documented in association with recessive magnesium disorders. Because the gene is large and encodes a complex multi-domain protein, variants can occur throughout the coding sequence, affecting different aspects of channel assembly, ion selectivity, or regulatory control.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TRPM6 cause hypomagnesaemia with secondary hypocalcaemia, a rare metabolic disorder characterised by severely low magnesium levels that in turn depress calcium concentrations. Clinical features typically begin in infancy and include muscle spasms, tetany, and generalised seizures. Without prompt recognition and lifelong magnesium supplementation, affected individuals may experience developmental delay and recurrent neurological crises. The condition underscores the critical dependency of normal neuromuscular and metabolic function on adequate magnesium availability.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TRPM6 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
TRPM6 appears on several NHS Genomic Medicine Service panels with green (high evidence) classification. It is included in the Early Onset or Syndromic Epilepsy panel (R59), reflecting its role in infantile seizure disorders secondary to magnesium deficiency. The gene also features on the Likely Inborn Error of Metabolism panel (R98), the Renal Tubulopathies panel (R198), and the Undiagnosed Metabolic Disorders panel, all recognising TRPM6-related hypomagnesaemia as a clinically significant and actionable inherited metabolic condition within the NHS genomic testing framework.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the TRPM6 gene do?
TRPM6 encodes a magnesium channel protein that controls the absorption of magnesium in the intestine and its reabsorption in the kidney. This regulation is essential for maintaining normal magnesium levels, which support hundreds of enzymatic reactions throughout the body.
How are TRPM6 variants inherited?
Pathogenic variants in TRPM6 are inherited in an autosomal recessive pattern, meaning an individual must inherit a mutation from both parents to develop hypomagnesaemia with secondary hypocalcaemia. Carriers, who have one variant copy, typically remain unaffected.
What are the signs of TRPM6-related magnesium deficiency?
Affected individuals usually present in infancy with severe low magnesium and low calcium levels, leading to muscle spasms, tremor, and seizures. Early diagnosis and lifelong magnesium supplementation are critical to prevent neurological complications and support normal development.