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SLC25A15
solute carrier family 25 member 15
The SLC25A15 gene provides instructions for mitochondrial ornithine transporter 1, a protein vital for nitrogen waste processing in the urea cycle, with variants associated with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome. The SLC25A15 gene encodes a protein called mitochondrial ornithine transporter 1 (ORNT1), which plays a key role in the urea cycle.
SLC25A15 is located on the long (q) arm of chromosome 13, at band 13q14.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The SLC25A15 gene, also known as ORNT1, provides the genetic blueprint for mitochondrial ornithine transporter 1. This protein is a critical component of the urea cycle, a series of biochemical reactions that occur primarily in liver cells. The urea cycle is responsible for detoxifying ammonia, a harmful byproduct of protein metabolism, by converting it into urea for excretion.
Disruptions to the function of mitochondrial ornithine transporter 1 due to variants in the SLC25A15 gene can lead to the accumulation of ammonia in the blood, which is particularly toxic to the nervous system. This can result in conditions such as HHH syndrome, an inherited metabolic disorder.
What the gene does
The SLC25A15 gene directs the production of mitochondrial ornithine transporter 1, a protein localised to the inner membrane of mitochondria. Mitochondria are often referred to as the 'powerhouses' of the cell, generating energy through cellular respiration.
The primary function of mitochondrial ornithine transporter 1 is to transport ornithine, a key molecule, from the cytoplasm into the mitochondrial matrix. Once inside the mitochondrial matrix, ornithine participates in the urea cycle. This metabolic pathway is essential for processing and eliminating excess nitrogen, which is generated when the body breaks down proteins. By converting ammonia into less toxic urea, the protein encoded by SLC25A15 helps prevent harmful levels of ammonia from accumulating in the bloodstream and tissues.
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Chromosome location
The SLC25A15 gene is situated on chromosome 13, specifically at band 13q14.11. Chromosomes are organised structures of DNA and proteins found within cells, carrying genetic information. The precise location on chromosome 13 helps in understanding its genetic context and how it might be inherited.
Protein structure
The protein encoded by the SLC25A15 gene, mitochondrial ornithine transporter 1, consists of 301 amino acids. It features a characteristic organisation of repeated domains, typical for mitochondrial carrier proteins. These include three distinct Solcar repeats: Solcar 1, spanning amino acids 7-91; Solcar 2, located from amino acids 104-197; and Solcar 3, found between amino acids 207-293. These repeats are crucial for the protein's function in transporting molecules across the mitochondrial membrane.
Key variants
Variants in the SLC25A15 gene can alter the structure or function of the mitochondrial ornithine transporter 1 protein. These genetic changes can impair the protein's ability to transport ornithine effectively, leading to metabolic dysfunction. Such variants are typically inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop an associated condition.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.112C>T | p.Gln38Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.265C>T | p.Gln89Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.326del | p.Asn109fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.523dup | p.Ser175fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.594dup | p.Ala199fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.623-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.755_756insA | p.Phe253fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
c.781+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | SLC25A15-related disorder |
c.98_101del | p.Met33fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the SLC25A15 gene are primarily associated with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome. This is a rare, inherited metabolic disorder characterised by elevated levels of ornithine and ammonia in the blood, and homocitrulline in the urine. Symptoms can vary but often include neurological impairment, developmental delay, and episodes of lethargy or vomiting, particularly in response to high protein intake. Early diagnosis and management are crucial for individuals affected by HHH syndrome.
Inheritance pattern
Conditions caused by pathogenic SLC25A15 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
The SLC25A15 gene is recognised within the UK's NHS Genomic Medicine Service pathways, indicating its clinical significance. It is listed as 'green' on PanelApp for several conditions, including DDG2P, hereditary spastic paraplegia (adult and childhood onset), hyperammonaemia, intellectual disability, likely inborn error of metabolism, and undiagnosed metabolic disorders. This green status signifies that there is sufficient evidence to support routine testing of this gene for these conditions in a clinical diagnostic setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the SLC25A15 gene?
The SLC25A15 gene provides instructions for making mitochondrial ornithine transporter 1, a protein that transports ornithine into mitochondria. This process is essential for the urea cycle, which detoxifies harmful ammonia by converting it into urea for excretion.
What condition is associated with variants in the SLC25A15 gene?
Pathogenic variants in the SLC25A15 gene are associated with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome. This is a rare metabolic disorder characterised by high levels of ornithine and ammonia in the blood, and homocitrulline in the urine.
How is HHH syndrome inherited?
HHH syndrome is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic variant in the SLC25A15 gene, one from each parent, to develop the condition.
References
- Waisbren SE, Gropman AL, Members of the Urea Cycle Disorders Consortium (UCDC). Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. Journal of inherited metabolic disease. 2016. PMID: 27215558
- Martinelli D, Diodato D, Ponzi E. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet journal of rare diseases. 2015. PMID: 25874378
- Camacho JA, Mardach R, Rioseco-Camacho N. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatric research. 2006. PMID: 16940241
- Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Archiv : European journal of physiology. 2004. PMID: 14598172
- Camacho JA, Rioseco-Camacho N, Andrade D. Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Molecular genetics and metabolism. 2003. PMID: 12948741
- Miyamoto T, Kanazawa N, Kato S. Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. Journal of human genetics. 2001. PMID: 11355015
- Camacho JA, Obie C, Biery B. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nature genetics. 1999. PMID: 10369256