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MFSD8
major facilitator superfamily domain containing 8
The MFSD8 gene provides instructions for a protein thought to be involved in transporting molecules across lysosomal membranes, and pathogenic variants are associated with CLN7 disease (Batten disease). The MFSD8 gene encodes a protein that belongs to the major facilitator superfamily, a group of proteins known for transporting molecules.
MFSD8 is located on the long (q) arm of chromosome 4, at band 4q28.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The MFSD8 gene, or major facilitator superfamily domain containing 8, provides the genetic blueprint for a protein integrated into the membranes of lysosomes. Lysosomes are cellular compartments responsible for breaking down and recycling various molecules. Although the exact molecules transported by the MFSD8 protein are not yet identified, it is understood to be a member of the major facilitator superfamily of secondary active transporter proteins, which generally move specific substances within or between cells.
Dysfunction of the MFSD8 protein due to genetic changes is primarily associated with CLN7 disease, a form of Batten disease, which is a severe neurodegenerative disorder.
What the gene does
The MFSD8 gene encodes a protein that is localised within the lysosomal membrane. Lysosomes are vital organelles within cells, acting as the primary sites for degradation and recycling of cellular waste products, macromolecules, and organelles. The MFSD8 protein is classified as a member of the major facilitator superfamily, a large family of membrane transport proteins that facilitate the movement of diverse substrates across biological membranes.
While the specific substrates transported by the MFSD8 protein remain unconfirmed, its classification suggests it likely plays a crucial role in regulating the movement of certain molecules into or out of lysosomes. This transport activity is essential for maintaining normal lysosomal function and cellular homeostasis. Impaired function of the MFSD8 protein is thought to disrupt these vital lysosomal processes, leading to the accumulation of waste materials within cells, particularly in the brain, which contributes to the pathology of associated conditions.
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Chromosome location
The MFSD8 gene is situated on the long arm (q) of chromosome 4, specifically at position 4q28.2. This location refers to the precise address of the gene within the human genome.
Protein structure
The MFSD8 protein comprises 518 amino acids. It features a Disordered region at amino acids 1-20, indicating a segment that lacks a fixed three-dimensional structure and may be involved in protein-protein interactions or regulatory functions. Additionally, a Dileucine internalization motif is present at amino acids 13-14, which is typically involved in the internalisation and trafficking of membrane proteins.
Key variants
Genetic variations, or variants, within the MFSD8 gene can alter the protein's structure and function. These changes can lead to its reduced efficiency or complete loss of function, thereby disrupting critical lysosomal processes. Pathogenic variants in MFSD8 are primarily inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene (one from each parent) to develop an associated condition.
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.1102+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Late-infantile neuronal ceroid lipofuscinosis |
c.1158_1167del | p.Trp387fs | Pathogenic/Likely pathogenic | ★★☆☆ | Late-infantile neuronal ceroid lipofuscinosis |
c.1337del | p.Gly446fs | Pathogenic/Likely pathogenic | ★★☆☆ | Late-infantile neuronal ceroid lipofuscinosis |
c.1412del | p.Phe471fs | Pathogenic/Likely pathogenic | ★★☆☆ | Late-infantile neuronal ceroid lipofuscinosis |
c.531_537del | p.Gly179fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis 7 |
c.593_594del | p.Val198fs | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis 7 |
c.600G>A | p.Trp200Ter | Pathogenic | ★★☆☆ | Neuronal ceroid lipofuscinosis 7 |
c.77T>G | p.Leu26Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Macular dystrophy with central cone involvement |
c.910C>T | p.Gln304Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Macular dystrophy with central cone involvement |
c.979del | p.Val327fs | Pathogenic | ★★☆☆ | Late-infantile 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 MFSD8 gene are known to cause CLN7 disease, a severe form of neuronal ceroid lipofuscinosis, also referred to as Batten disease. This condition typically manifests in early childhood and is characterised by progressive neurological decline. Symptoms often include developmental regression, recurrent seizures (epilepsy), involuntary muscle twitches (myoclonus), difficulties with coordination (ataxia), speech impairment, and vision loss. The disease progresses to affect mental and motor skills significantly.
UK clinical status
The MFSD8 gene is included in several Green RAG status panels within the UK National Health Service (NHS) Genomic Medicine Service. These panels indicate that there is sufficient evidence for routine clinical testing of this gene for specific conditions. It is part of panels for conditions such as Ataxia and cerebellar anomalies - childhood onset, Early onset or syndromic epilepsy, Hereditary ataxia (adult onset), Intellectual disability, and Neuronal ceroid lipofuscinosis (R231). It is also assessed under panels for DDG2P, Likely inborn error of metabolism (R98), Lysosomal storage disorder (R276), Retinal disorders (R32), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the MFSD8 gene?
The MFSD8 gene provides instructions for making a protein that is located in the membrane of lysosomes, which are cellular compartments responsible for waste breakdown and recycling. It is believed to transport specific molecules across the lysosomal membrane, though the exact molecules are still being researched.
What is CLN7 disease?
CLN7 disease is a severe, progressive neurodegenerative disorder caused by pathogenic variants in the MFSD8 gene. It typically begins in early childhood, leading to symptoms such as developmental regression, seizures, coordination difficulties, speech problems, and vision loss.
How is CLN7 disease inherited?
CLN7 disease is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered MFSD8 gene, one from each parent, to develop the condition. Parents who each carry one copy of the altered gene are typically unaffected but can pass the condition on to their children.
References
- Steenhuis P, Froemming J, Reinheckel T. Proteolytic cleavage of the disease-related lysosomal membrane glycoprotein CLN7. Biochimica et biophysica acta. 2012. PMID: 22668694
- Sharifi A, Kousi M, Sagné C. Expression and lysosomal targeting of CLN7, a major facilitator superfamily transporter associated with variant late-infantile neuronal ceroid lipofuscinosis. Human molecular genetics. 2010. PMID: 20826447
- Kousi M, Siintola E, Dvorakova L. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain : a journal of neurology. 2009. PMID: 19201763
- Siintola E, Topcu M, Aula N. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. American journal of human genetics. 2007. PMID: 17564970