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CLN6
CLN6 transmembrane ER protein
The CLN6 gene provides instructions for a protein located in the endoplasmic reticulum, which is thought to be involved in the transport of various cellular components. The CLN6 gene's primary function is not yet fully understood, but it is believed to play a role in regulating the movement of specific proteins and fats from the endoplasmic reticulum to lysosomes.
CLN6 is located on the long (q) arm of chromosome 15, at band 15q23. Arm ratio per GRCh38 - banding schematic.
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Overview
The CLN6 gene codes for a transmembrane protein of the endoplasmic reticulum and is associated with Batten disease (CLN6), an inherited neurodegenerative disorder. Although the precise biological role of this protein remains incompletely characterised, it localises to the endoplasmic reticulum, an organelle essential for processing and transporting proteins within cells.
What the gene does
The endoplasmic reticulum houses the protein encoded by CLN6, where it appears to participate in managing how certain lipids and proteins move through the cell. Evidence suggests the protein coordinates transport from the endoplasmic reticulum to lysosomes, the cellular compartments that break down and recycle unwanted materials. By facilitating this movement, the CLN6 protein likely supports the cell's ability to dispose of substances no longer required for normal function, thereby maintaining cellular homeostasis.
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Chromosome location
The CLN6 gene is found on chromosome 15 at region 15q23. This specific chromosomal location dictates its position within the human genome.
Protein structure
The CLN6 protein comprises 311 amino acids. Detailed experimental characterisation of its domain architecture has not been extensively reported.
Key variants
Variants within the CLN6 gene can impair the normal function of its encoded protein, leading to health conditions. More than 70 pathogenic changes have been documented in this gene, many of which result in a truncated or dysfunctional protein that cannot adequately support cellular waste disposal processes.
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.168G>A | p.Trp56Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6A |
c.180_181del | p.Phe60fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.195dup | p.Met66fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6B (Kufs type) |
c.358_366del | p.Phe120_Met122del | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6A |
c.396dup | p.Val133fs | Pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.397_398del | p.Val133fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.516T>A | p.Tyr172Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6A |
c.712_713delinsAC | p.Phe238Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6A |
c.827G>A | p.Trp276Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ceroid lipofuscinosis, neuronal, 6A |
c.829_836delinsCCT | p.Val277fs | 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 CLN6 gene are primarily linked to Batten disease (CLN6), an inherited neurodegenerative disorder that follows an autosomal recessive pattern. Individuals carrying two pathogenic variants typically experience declining motor and cognitive abilities, with onset generally occurring during early to late childhood. This progressive condition leads to worsening difficulties with movement coordination and a gradual reduction in intellectual capacity.
Inheritance pattern
Conditions caused by pathogenic CLN6 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 CLN6 gene is included on several national panels within the NHS Genomic Medicine Service, reflecting its clinical importance in the UK. These panels cover conditions such as Neuronal ceroid lipofuscinosis, Adult onset neurodegenerative disorder, Intellectual disability, Lysosomal storage disorder, and Hereditary ataxia. This inclusion means that CLN6 is routinely analysed in clinical settings for individuals presenting with symptoms consistent with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the CLN6 gene?
The CLN6 gene codes for a protein located in the endoplasmic reticulum. It is thought to regulate the transport of specific proteins and fats from the endoplasmic reticulum to lysosomes, which are crucial for the cell's waste removal processes.
What condition is associated with CLN6 gene variants?
Pathogenic variants in the CLN6 gene are associated with Batten disease (CLN6), a neurodegenerative disorder that typically affects motor and mental development from childhood, leading to progressive neurological decline.
How is Batten disease (CLN6) inherited?
Batten disease (CLN6) follows an autosomal recessive inheritance pattern. This means an individual must inherit two pathogenic variants, one from each parent, to develop the condition. Individuals with only one pathogenic variant are typically carriers and do not show symptoms.
References
- Sato R, Inui T, Endo W. First Japanese variant of late infantile neuronal ceroid lipofuscinosis caused by novel CLN6 mutations. Brain & development. 2016. PMID: 27165443
- Canafoglia L, Gilioli I, Invernizzi F. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology. 2015. PMID: 26115733
- Arsov T, Smith KR, Damiano J. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. American journal of human genetics. 2011. PMID: 21549341
- Kay C. Same gene, surprising difference: adult neuronal ceroid lipofuscinosis linked to CLN6, mutated in variant late-infantile form. Clinical genetics. 2011. PMID: 21819394
- Kurze AK, Galliciotti G, Heine C. Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6. Human mutation. 2010. PMID: 20020536
- Cannelli N, Garavaglia B, Simonati A. Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6. Biochemical and biophysical research communications. 2009. PMID: 19135028