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CLN8
CLN8 transmembrane ER and ERGIC protein
The CLN8 gene provides instructions for a protein thought to be involved in transport within cells, particularly in the endoplasmic reticulum, and is associated with Batten disease. The CLN8 gene encodes a transmembrane protein located primarily in the endoplasmic reticulum, a cellular structure crucial for protein and lipid processing.
CLN8 is located on the short (p) arm of chromosome 8, at band 8p23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The CLN8 gene, also known as CLN8 transmembrane ER and ERGIC protein, plays a role in cellular functions, particularly within the endoplasmic reticulum. It is classified under the neuronal ceroid lipofuscinosis group of genes due to its association with Batten disease, an inherited neurodegenerative condition. Understanding the CLN8 gene's function is important for comprehending the mechanisms underlying these complex disorders.
What the gene does
The protein encoded by the CLN8 gene is believed to facilitate transport within cells, specifically moving materials into and out of the endoplasmic reticulum. The endoplasmic reticulum is a vital organelle involved in the production, processing, and transport of proteins. Beyond its transport role, the CLN8 protein may also contribute to the regulation of lipid levels within cells by the endoplasmic reticulum. In certain cell types, such as nerve cells, the CLN8 protein is thought to be active outside the endoplasmic reticulum, though its precise function in these locations is not yet fully understood.
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Chromosome location
The CLN8 gene is situated on chromosome 8, specifically at the band 8p23.3. This genomic location provides a physical address for the gene within the human genome, assisting in genetic mapping and the identification of variants associated with inherited conditions.
Protein structure
The CLN8 protein has a length of 286 amino acids. Key structural features include a large TLC domain spanning amino acids 62-262, which is central to its function. Additionally, an ER-retrieval signal motif is located at amino acids 283-286, which is typically involved in returning proteins to the endoplasmic reticulum.
Key variants
Variants in the CLN8 gene can lead to altered protein function, which may disrupt normal cellular processes. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact on protein activity can vary, contributing to the clinical diversity observed in associated conditions.
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.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.208C>T | p.Arg70Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.295C>T | p.Gln99Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.29C>G | p.Ser10Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.312G>A | p.Trp104Ter | Pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.398T>A | p.Leu133Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis |
c.499G>T | p.Glu167Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CLN8-related disorder |
c.593_596dup | p.Met200fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis 8 |
c.703del | p.Val236fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.709G>A | p.Gly237Arg | Pathogenic/Likely pathogenic | ★★☆☆ | CLN8-related disorder |
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 CLN8 gene are linked to Batten disease (CLN8), an inherited disorder primarily affecting the nervous system. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two altered copies of the gene, one from each parent, to develop the condition. The severity of Batten disease (CLN8) can vary, but typically involves progressive neurological symptoms.
Inheritance pattern
Conditions caused by pathogenic CLN8 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 CLN8 gene is included in several NHS Genomic Medicine Service national test panels in the UK. It is listed as 'green' on panels such as DDG2P, Early onset or syndromic epilepsy, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Neuronal ceroid lipofuscinosis, Retinal disorders, and Undiagnosed metabolic disorders, indicating that it is routinely analysed in a clinical context for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CLN8 gene?
The CLN8 gene provides instructions for a protein that is thought to be involved in the transport of materials within cells, particularly into and out of the endoplasmic reticulum, and may also help regulate lipid levels.
What condition is associated with variants in the CLN8 gene?
Variants in the CLN8 gene are associated with Batten disease (CLN8), an inherited neurological disorder that affects the nervous system and is categorised as a neuronal ceroid lipofuscinosis.
How is Batten disease (CLN8) inherited?
Batten disease (CLN8) is inherited in an autosomal recessive manner, meaning an individual must inherit two altered copies of the CLN8 gene, one from each parent, to be affected by the condition.
References
- Passantino R, Cascio C, Deidda I. Identifying protein partners of CLN8, an ER-resident protein involved in neuronal ceroid lipofuscinosis. Biochimica et biophysica acta. 2013. PMID: 23142642
- Reinhardt K, Grapp M, Schlachter K. Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis. Clinical genetics. 2010. PMID: 19807737
- Vantaggiato C, Redaelli F, Falcone S. A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. Human mutation. 2009. PMID: 19431184
- Ranta S, Topcu M, Tegelberg S. Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Human mutation. 2004. PMID: 15024724