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SCARB2
scavenger receptor class B member 2
SCARB2 is located on the long (q) arm of chromosome 4, at band 4q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
SCARB2 encodes lysosomal integral membrane protein-2 (LIMP-2), a transmembrane protein primarily located within lysosomal membranes. Lysosomes function as cellular recycling centres, breaking down various biological materials for reuse or disposal. The LIMP-2 protein serves dual roles: it acts as a molecular chaperone for the enzyme beta-glucocerebrosidase, guiding it from the endoplasmic reticulum to lysosomes, and contributes to maintaining lysosomal membrane stability once delivery is complete.
Pathogenic variants in SCARB2 are associated with action myoclonus-renal failure syndrome, a rare autosomal recessive condition characterised by involuntary muscle jerking and progressive kidney dysfunction. The gene is located on chromosome 4q21.1 and is included in several NHS Genomic Medicine Service gene panels for neurological and renal disorders.
What the gene does
The SCARB2-encoded protein functions principally as a lysosomal membrane component spanning 478 amino acids. Within the endoplasmic reticulum, LIMP-2 binds to beta-glucocerebrosidase and facilitates its transport to lysosomes, where this enzyme degrades glucocerebroside, a fatty substance that accumulates if not properly processed. After delivering its cargo, LIMP-2 remains embedded in the lysosomal membrane, where it contributes to the structural stability of these organelles.
Beyond lysosomes, LIMP-2 appears in intercalated discs within cardiac muscle, where it connects individual heart cells into functional fibres. Research suggests the protein may have a role when the heart experiences stress from enlargement, though the precise mechanism remains under investigation. The protein also localises to the outer cell membrane in some tissues, where it can serve as an entry point for certain enteroviruses, including those responsible for hand, foot, and mouth disease. This viral receptor function demonstrates the protein's structural accessibility at the cell surface.
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Chromosome location
SCARB2 resides on the long arm of chromosome 4 at position 21.1 (4q21.1). This chromosomal region contains multiple genes involved in cellular metabolism and membrane trafficking. The gene encodes a protein of 478 amino acids that undergoes processing and glycosylation before reaching its functional destination in lysosomal membranes.
Protein structure
The SCARB2 protein contains a region spanning amino acids 155-191 that is important for interaction with GBA1, the gene encoding beta-glucocerebrosidase. This binding domain enables LIMP-2 to recognise and attach to the enzyme within the endoplasmic reticulum, forming a complex that travels together to lysosomes. The protein's structure includes transmembrane segments that anchor it within lipid bilayers, allowing it to function both as a transport chaperone and as a permanent membrane component. The protein undergoes glycosylation, contributing to its identification as an 85-kilodalton lysosomal sialoglycoprotein.
Key variants
More than 20 pathogenic variants in SCARB2 have been reported in association with action myoclonus-renal failure syndrome. These variants follow an autosomal recessive inheritance pattern, meaning affected individuals typically carry alterations in both gene copies. The variants identified to date include missense changes, frameshift mutations, and other alterations that impair the protein's ability to transport beta-glucocerebrosidase or maintain lysosomal integrity.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
SCARB2 variants are primarily associated with action myoclonus-renal failure syndrome (AMRF), a rare progressive disorder. Individuals with this condition experience episodes of involuntary muscle jerking, particularly when attempting purposeful movements - a phenomenon known as action myoclonus. Progressive kidney disease develops in many affected individuals, though the severity and age of onset vary. The neurological features result from impaired lysosomal function in neurons, whilst the renal manifestations reflect similar dysfunction within kidney cells. Both symptom domains stem from the loss of effective LIMP-2-mediated enzyme transport and lysosomal stability.
Inheritance pattern
Conditions caused by pathogenic SCARB2 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
Within the NHS Genomic Medicine Service, SCARB2 holds green classification status on multiple gene panels. It appears on the early onset or syndromic epilepsy panel (R59), the hereditary neuropathy or pain disorder panel (R78), and the proteinuric renal disease panel (R195), as well as the unexplained kidney failure in young people panel. Green status indicates strong evidence linking the gene to the specified clinical presentations, supporting its inclusion in NHS genomic testing pathways for patients with relevant symptoms.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for SCARB2-related conditions?
SCARB2-associated action myoclonus-renal failure syndrome follows an autosomal recessive inheritance pattern. This means an individual must inherit a pathogenic variant from both parents to develop the condition. Carriers with a single variant typically remain asymptomatic.
How does SCARB2 relate to Gaucher disease?
SCARB2 encodes the protein that transports beta-glucocerebrosidase, the enzyme deficient in Gaucher disease. Whilst Gaucher disease results from variants in GBA1 (the enzyme gene), SCARB2 variants impair the delivery of normal enzyme to lysosomes, producing overlapping metabolic consequences through a different mechanism.
Why does SCARB2 dysfunction affect both the brain and kidneys?
Both neurons and kidney cells rely heavily on lysosomal function to process cellular waste. When LIMP-2 cannot effectively transport beta-glucocerebrosidase or maintain lysosomal stability, both tissue types accumulate metabolic byproducts, leading to the neurological and renal features characteristic of AMRF syndrome.
References
- Gonzalez A, Valeiras M, Sidransky E. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Molecular genetics and metabolism. 2014. PMID: 24389070
- Dang M, Wang X, Wang Q. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein & cell. 2014. PMID: 24986489
- Dibbens LM, Michelucci R, Gambardella A. SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure. Annals of neurology. 2009. PMID: 19847901
- Berkovic SF, Dibbens LM, Oshlack A. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. American journal of human genetics. 2008. PMID: 18308289
- Balreira A, Gaspar P, Caiola D. A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome. Human molecular genetics. 2008. PMID: 18424452
- Schroen B, Leenders JJ, van Erk A. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy. The Journal of experimental medicine. 2007. PMID: 17485520