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SLC25A13
solute carrier family 25 member 13
The SLC25A13 gene provides instructions for producing citrin, a protein crucial for transporting molecules across mitochondrial membranes, particularly in the liver, kidneys, and heart. SLC25A13 encodes the citrin protein, which plays a vital role in cellular metabolism by facilitating the movement of glutamate into and aspartate out of mitochondria.
SLC25A13 is located on the long (q) arm of chromosome 7, at band 7q21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The SLC25A13 gene, also known as CITRIN, provides the genetic blueprint for a protein called citrin. This protein is primarily active in key metabolic organs such as the liver, kidneys, and heart. Citrin's main function involves the transport of specific molecules into and out of mitochondria, the cell's energy-producing organelles. This critical transport activity underpins several fundamental metabolic processes, including the urea cycle and the synthesis of various cellular building blocks.
Disruptions in the SLC25A13 gene, typically through inherited genetic variants, can impair citrin's function. Such impairments can lead to metabolic disturbances that affect the body's ability to process certain compounds, with notable implications for conditions like Citrullinaemia type II.
What the gene does
The SLC25A13 gene produces citrin, a mitochondrial carrier protein that facilitates the movement of molecules across the inner mitochondrial membrane. Specifically, citrin functions as part of the malate-aspartate shuttle, transporting glutamate into mitochondria and aspartate out of them. This shuttling mechanism is critical for maintaining cellular energy production and metabolic balance.
One of citrin's key roles is to ensure an adequate supply of aspartate outside the mitochondria, which is necessary for the proper functioning of the urea cycle. The urea cycle, which occurs in liver cells, is essential for detoxifying excess nitrogen by converting it into urea for excretion. Beyond the urea cycle, citrin also contributes to processes involved in the breakdown and synthesis of simple sugars, protein production, and the creation of nucleotides, the fundamental building blocks of DNA and RNA.
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Chromosome location
The SLC25A13 gene is located on chromosome 7, specifically at position 7q21.3. This designation refers to the long (q) arm of chromosome 7, within region 21, band 3. The precise location on the chromosome helps in mapping and understanding genetic variations associated with this gene.
Protein structure
The citrin protein, encoded by SLC25A13, is composed of 675 amino acids and features several distinct domains. It includes a Regulatory N-terminal domain (amino acids 2-295), which contains four EF-hand domains: EF-hand 1 (amino acids 51-86), EF-hand 2 (amino acids 87-122), EF-hand 3 (amino acids 125-157), and EF-hand 4 (amino acids 158-193). Following this is a Linker loop domain (amino acids 296-311). The core transport function resides within the Carrier domain (amino acids 321-612), which itself contains three Solcar repeats: Solcar 1 (amino acids 326-418), Solcar 2 (amino acids 426-510), and Solcar 3 (amino acids 518-606). The protein concludes with a C-terminal domain (amino acids 613-675).
Key variants
Variants within the SLC25A13 gene can alter the structure or function of the citrin protein. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. Pathogenic variants typically lead to a non-functional or unstable citrin protein, which is rapidly degraded, or to the production of an abnormally short protein that cannot perform its intended role in mitochondrial transport.
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.1230+1G>C | - | Pathogenic | ★★☆☆ | Citrullinemia |
c.1610_1612delinsAT | p.Leu537fs | Pathogenic | ★★☆☆ | Citrullinemia, type II, adult-onset |
c.1793T>G | p.Leu598Arg | Pathogenic | ★★☆☆ | Citrullinemia type II |
c.1800C>A | p.Tyr600Ter | Pathogenic | ★★☆☆ | Citrullinemia |
c.316G>T | p.Glu106Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Citrin deficiency |
c.577dup | p.His193fs | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia, type II, adult-onset |
c.615+1G>A | - | Pathogenic | ★★☆☆ | Citrin deficiency |
c.755-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia, type II, adult-onset |
c.848+1del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Citrullinemia, type II, adult-onset |
c.89dup | p.Asn30fs | Pathogenic/Likely pathogenic | ★★☆☆ | Citrin deficiency |
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 SLC25A13 gene are primarily associated with an autosomal recessive condition known as Citrullinaemia type II, also referred to as citrin deficiency. This condition manifests with a range of symptoms, particularly neurological issues, which often begin in adulthood. The impaired function of citrin leads to metabolic imbalances, affecting the urea cycle and other critical pathways.
Inheritance pattern
Conditions caused by pathogenic SLC25A13 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 SLC25A13 gene is recognised within several NHS Genomic Medicine Service national test directory panels, indicating its clinical significance in the UK. It holds a 'green' RAG (Red Amber Green) rating for conditions such as Cholestasis (R171), Hyperammonaemia, Neonatal cholestasis, and Undiagnosed metabolic disorders (R98). It is also listed within the DDG2P (Deciphering Developmental Disorders) gene list and is associated with 'Likely inborn error of metabolism', signifying its established role in these clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the SLC25A13 gene?
The SLC25A13 gene provides instructions for making the citrin protein, which is essential for transporting molecules, specifically glutamate and aspartate, across the mitochondrial membrane. This process is crucial for the urea cycle and other metabolic functions.
What condition is associated with variants in the SLC25A13 gene?
Variants in the SLC25A13 gene are primarily associated with Citrullinaemia type II, also known as citrin deficiency. This is an autosomal recessive condition that affects metabolism and can lead to neurological symptoms, typically in adulthood.
Where in the body is the citrin protein most active?
The citrin protein, encoded by SLC25A13, is chiefly active in organs with high metabolic demands, such as the liver, kidneys, and heart. In these organs, it plays a vital role in cellular energy production and waste processing.
References
- Song YZ, Zhang ZH, Lin WX. SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. PloS one. 2013. PMID: 24069319
- Song YZ, Deng M, Chen FP. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. International journal of molecular medicine. 2011. PMID: 21424115
- Lu YB, Kobayashi K, Ushikai M. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. Journal of human genetics. 2005. PMID: 16059747
- Saheki T, Kobayashi K, Iijima M. Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatology research : the official journal of the Japan Society of Hepatology. 2005. PMID: 16199199
- Saheki T, Kobayashi K, Iijima M. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Molecular genetics and metabolism. 2004. PMID: 15050970
- Kobayashi K, Bang Lu Y, Xian Li M. Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Molecular genetics and metabolism. 2003. PMID: 14680984
- Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). Journal of human genetics. 2002. PMID: 12111366
- Saheki T, Kobayashi K, Iijima M. Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency. Metabolic brain disease. 2002. PMID: 12602510