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CTNS
cystinosin, lysosomal cystine transporter
The CTNS gene encodes the cystinosin protein, a lysosomal transporter essential for removing the amino acid cystine from cellular compartments, playing a key role in metabolic health. The CTNS gene provides instructions for producing cystinosin, a protein vital for cellular function.
CTNS is located on the short (p) arm of chromosome 17, at band 17p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The CTNS gene, also known as cystinosin, lysosomal cystine transporter, is crucial for human health. It provides the genetic blueprint for a protein called cystinosin. This protein plays a fundamental role in cellular metabolism by regulating the movement of cystine, an amino acid, out of lysosomes.
Maintaining proper cystine transport is essential for preventing its harmful accumulation within cells. Conditions arise when the CTNS gene does not function correctly, highlighting its importance in preventing certain inherited metabolic disorders.
What the gene does
The CTNS gene instructs the cell to produce cystinosin, a transport protein located in the membrane of lysosomes. Lysosomes are cellular compartments that function as recycling centres, breaking down and digesting various cellular materials. After these materials, including proteins, are broken down into smaller components like amino acids, they need to be transported out of the lysosome to be reused by the cell.
Cystinosin specifically mediates the efflux of the amino acid cystine from the lysosomal interior into the cytoplasm. This targeted transport ensures that cystine does not build up to toxic levels within the lysosome. Proper functioning of cystinosin is therefore critical for maintaining cellular homeostasis and preventing the accumulation of cystine, which can lead to cellular damage and disease.
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Chromosome location
The CTNS gene is situated on chromosome 17, specifically at position 17p13.2. This location refers to the short arm (p) of chromosome 17, within band 13.2. The gene encompasses a total of 12 exons.
Protein structure
The cystinosin protein is composed of 367 amino acids and is characterised by several key functional regions. It features two PQ-loop domains: PQ-loop 1, spanning amino acids 123-189, and PQ-loop 2, located between amino acids 263-328. These domains are typically associated with transporter function. Additionally, the protein includes a Lysosomal targeting motif, found at amino acids 362-366, which directs the protein to its correct cellular location within the lysosomal membrane.
Key variants
Genetic variations, or variants, within the CTNS gene can alter the structure or function of the cystinosin protein. These variants can range from small changes in single DNA building blocks to larger deletions affecting significant portions of the gene. Such alterations can impair the protein's ability to transport cystine effectively, leading to its accumulation.
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.1000del | p.Thr334fs | Pathogenic/Likely pathogenic | ★★☆☆ | CTNS-related disorder |
c.1013T>G | p.Leu338Arg | Pathogenic | ★★☆☆ | Cystinosis |
c.1027_1038del | p.Ile343_Asp346del | Pathogenic/Likely pathogenic | ★★☆☆ | Cystinosis |
c.141-24T>C | - | Pathogenic | ★★☆☆ | Nephropathic cystinosis |
c.15G>A | p.Trp5Ter | Pathogenic | ★★☆☆ | Nephropathic cystinosis |
c.225+3A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephropathic cystinosis |
c.27del | p.Phe9fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.751_752del | p.Thr251fs | Pathogenic | ★★☆☆ | Juvenile nephropathic cystinosis |
c.955C>T | p.Gln319Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cystinosis |
c.970+5G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
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
Variants in the CTNS gene are directly associated with the inherited condition Cystinosis. This is an autosomal recessive disorder, meaning an individual must inherit two copies of a pathogenic CTNS variant (one from each parent) to develop the condition. The severity and presentation of Cystinosis can vary depending on the specific genetic variants inherited.
Inheritance pattern
Conditions caused by pathogenic CTNS 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 CTNS gene is well-recognised within the UK's genomic healthcare system. It is included in several NHS Genomic Medicine Service (GMS) approved panels, indicating its clinical significance for diagnosis and management. These panels include 'Cystinosis', 'DDG2P', 'Likely inborn error of metabolism', 'Lysosomal storage disorder', 'Renal tubulopathies', 'Undiagnosed metabolic disorders', and 'Unexplained kidney failure in young people'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the CTNS gene?
The CTNS gene provides instructions for making the cystinosin protein, which is a transporter located in the membrane of lysosomes. Its primary role is to move the amino acid cystine out of lysosomes.
What is Cystinosis?
Cystinosis is an inherited metabolic disorder caused by pathogenic variants in the CTNS gene. It results in the accumulation of cystine within lysosomes, leading to crystal formation and damage in various organs, including the kidneys and eyes.
How is Cystinosis inherited?
Cystinosis is inherited in an autosomal recessive manner. This means that an individual must inherit two altered copies of the CTNS gene, one from each parent, to develop the condition. Individuals with only one altered copy are typically carriers and do not show symptoms.
References
- Servais A, Morinière V, Grünfeld JP. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clinical journal of the American Society of Nephrology : CJASN. 2008. PMID: 18178779
- Wamelink MM, Struys EA, Jansen EE. Sedoheptulokinase deficiency due to a 57-kb deletion in cystinosis patients causes urinary accumulation of sedoheptulose: elucidation of the CARKL gene. Human mutation. 2008. PMID: 18186520
- Kalatzis V, Nevo N, Cherqui S. Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Human molecular genetics. 2004. PMID: 15128704
- Bendavid C, Kleta R, Long R. FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Human genetics. 2004. PMID: 15365816
- Haq MR, Kalatzis V, Gubler MC. Immunolocalization of cystinosin, the protein defective in cystinosis. Journal of the American Society of Nephrology : JASN. 2002. PMID: 12138135
- Kalatzis V, Antignac C. Cystinosis: from gene to disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002. PMID: 12401840
- Touchman JW, Anikster Y, Dietrich NL. The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome research. 2000. PMID: 10673275
- Anikster Y, Shotelersuk V, Gahl WA. CTNS mutations in patients with cystinosis. Human mutation. 1999. PMID: 10571941
- Town M, Jean G, Cherqui S. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nature genetics. 1998. PMID: 9537412