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CLN5
CLN5 lysosomal BMP synthase
The CLN5 gene provides instructions for a protein important for lysosomal function, and variants in CLN5 are associated with a form of Batten disease. The CLN5 gene is responsible for producing a protein that plays a role in the lysosomes, which are cellular compartments that break down and recycle waste materials.
CLN5 is located on the long (q) arm of chromosome 13, at band 13q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The CLN5 gene, also known as CLN5 lysosomal BMP synthase, codes for a protein whose precise cellular role is still being researched. This protein is primarily active within lysosomes, which are vital cellular organelles responsible for degrading and recycling various molecules. Dysregulation of CLN5 function is linked to neuronal ceroid lipofuscinosis type 5 (CLN5 disease), a neurodegenerative condition belonging to the group of disorders known as Batten disease.
What the gene does
The protein encoded by the CLN5 gene functions within the lysosomes, which are critical for cellular waste management. It is initially produced as an inactive precursor, or preprotein, containing additional segments that must be removed through a processing step to become active. Once activated, the CLN5 protein is transported to the lysosomes, where it is thought to participate in the breakdown and recycling of damaged or unneeded proteins within the cell. While its exact mechanism of action remains under investigation, research suggests it contributes to the overall process by which lysosomes digest cellular waste.
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Chromosome location
The CLN5 gene is situated on chromosome 13, specifically at position 13q22.3. This genomic location refers to the long arm (q) of chromosome 13, in region 22, band 3.
Protein structure
The CLN5 protein consists of 358 amino acids. It features a membrane-anchoring region spanning amino acids 304-343, which is important for its localisation and function within the cellular membrane systems, particularly in relation to the lysosomes.
Key variants
Variants in the CLN5 gene can impact the protein's function, potentially leading to health conditions. These genetic changes can range from single base pair substitutions to larger deletions or insertions, and their pathogenicity is assessed based on their predicted effect on protein structure and function, as well as clinical evidence.
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.404G>A | p.Trp135Ter | Pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.429del | p.Cys144fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis 5 |
c.431_432del | p.Cys144fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.441_442dup | p.His148fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.529G>T | p.Glu177Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.594G>A | p.Trp198Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.717dup | p.Asn240Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.913_914del | p.Leu305fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.982G>T | p.Glu328Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.987T>G | p.Tyr329Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
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 CLN5 gene are associated with Batten disease (CLN5, late infantile variant), a severe neurodegenerative disorder. This condition typically manifests in childhood, often around age five, though symptoms can emerge later. Affected individuals commonly experience progressive neurological decline, including impaired mental and motor development, vision loss, and recurrent seizures.
Inheritance pattern
Conditions caused by pathogenic CLN5 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 CLN5 gene is recognised within the NHS Genomic Medicine Service, with several PanelApp entries indicating its clinical relevance in the UK. It is listed as 'green' for panels including Ataxia and cerebellar anomalies - childhood onset, DDG2P, Dystonia, chorea or related movement disorder, childhood onset, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Neuronal ceroid lipofuscinosis, Retinal disorders, and Undiagnosed metabolic disorders, signifying that there is sufficient evidence for genes on these panels to be considered diagnostically relevant.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the CLN5 gene?
The CLN5 gene provides instructions for a protein that is processed and transported to lysosomes, cellular compartments responsible for breaking down and recycling various molecules within cells. Its precise role in this process is still being investigated.
What condition is associated with variants in the CLN5 gene?
Variants in the CLN5 gene are primarily associated with Batten disease (CLN5, late infantile variant), a neurodegenerative disorder characterised by progressive neurological symptoms, vision loss, and seizures.
How is Batten disease (CLN5 type) inherited?
Batten disease caused by CLN5 variants is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic CLN5 variant, one from each parent, to develop the condition.
References
- De Silva B, Adams J, Lee SY. Proteolytic processing of the neuronal ceroid lipofuscinosis related lysosomal protein CLN5. Experimental cell research. 2015. PMID: 26342652
- Kollmann K, Uusi-Rauva K, Scifo E. Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. Biochimica et biophysica acta. 2013. PMID: 23402926
- Larkin H, Ribeiro MG, Lavoie C. Topology and membrane anchoring of the lysosomal storage disease-related protein CLN5. Human mutation. 2013. PMID: 24038957
- Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012. PMID: 22778232
- Schmiedt ML, Bessa C, Heine C. The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. Human mutation. 2010. PMID: 20052765