Alternative titles; symbols
HGNC Approved Gene Symbol: SCARB2
SNOMEDCT: 764453009;
Cytogenetic location: 4q21.1 Genomic coordinates (GRCh38): 4:76,158,737-76,234,532 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q21.1 | Epilepsy, progressive myoclonic 4, with or without renal failure | 254900 | Autosomal recessive | 3 |
Calvo et al. (1995) isolated the human homolog of rat LIMPII, a lysosomal integral membrane glycoprotein, from a myeloid cell cDNA library. The open reading frame predicted an amino acid sequence of 478 amino acids, 85% identical to that of rat LIMPII and 100% identical to that of the human glycoprotein LGP85 sequence published by Fujita et al. (1992). Calvo et al. (1995) reported that their cDNA sequence differed from that of Fujita et al. (1992) in its 5-prime and 3-prime untranslated regions, probably due to polymorphisms and alternative polyadenylation sites. Northern blot analysis revealed that CD36L2 is expressed as transcripts of 2.2 and 4.5 kb in a variety of human cell lines. Calvo et al. (1995) noted variable expression depending on cell lineage.
Reczek et al. (2007) stated that LIMP2 is a type III transmembrane protein with an approximately 400-amino acid luminal domain, 2 transmembrane domains, and a 20-amino acid cytoplasmic C-terminal tail. Glycosidase treatment reduced the apparent molecular mass of mouse Limp2 from 75 kD to 54 kD, consistent with heavy glycosylation.
By PCR analysis of human-hamster hybrids, Calvo et al. (1995) mapped the CD36L2 gene to human chromosome 4. They stated that CD36 (173510), CD36L1 (601040), and CD36L2 represent a gene family, but that this family is not clustered in the genome; these genes map to chromosomes 7, 12, and 4, respectively.
Berkovic et al. (2008) identified the SCARB2 gene within a critical region on chromosome 4q13-q21 for action myoclonus-renal failure syndrome (AMRF; 254900).
Enterovirus-71 (EV71), along with coxsackievirus A16 (CVA16), is a causative agent of hand, foot, and mouth disease (HFMD), a common, usually self-limiting febrile illness of young children that can cause neurologic diseases. Yamayoshi et al. (2009) transfected an EV71-resistant mouse fibroblast cell line with DNA from a susceptible human rhabdomyosarcoma line and detected EV71-susceptible cells by infection with GFP-expressing EV71. Using microarray analysis of EV71-susceptible cells, they identified SCARB2 as a receptor for groups A, B, and C of EV71. Pull-down analysis indicated that the extracellular portion of SCARB2 directly and specifically bound EV71, as well as CVA16, but not poliovirus. Infection could be inhibited by monoclonal antibodies to SCARB2. Yamayoshi et al. (2009) concluded that SCARB2, a ubiquitously expressed protein, is involved in the pathogenesis of HFMD caused by EV71 and possibly by CVA16, which is less frequently associated with neurologic symptoms.
Reczek et al. (2007) stated that overexpression of LIMP2 causes enlargement of early endosomes and late endosomes/lysosomes and impairs membrane trafficking out of the enlarged compartment. They found that LIMP2 bound beta-glucosidase (beta-GC, or GBA; 606463), but not alpha-galactosidase (GLA; 300644) or alpha-glucosidase (GAA; 606800). Beta-GC and LIMP2 interacted in the endoplasmic reticulum, and both proteins traversed the Golgi and endocytic compartments together en route to lysosomes. In vitro, low pH attenuated binding between the 2 proteins, suggesting that acidic lysosomal pH facilitates dissociation of beta-GC from LIMP2. Cross-linking experiments with transfected COS cells suggested that the beta-GC-LIMP2 complex is about 250 kD in size, consistent with a 2:2 beta-GC:LIMP2 stoichiometry. Mutation analysis revealed that a coiled-coil motif within the luminal domain of LIMP2 was required for beta-GC binding. Knockdown of LIMP2 in HeLa cells via small interfering RNA significantly reduced lysosomal beta-GC content and resulted in mistargeting of beta-GC for secretion. Reczek et al. (2007) concluded that LIMP2 functions as a mannose-6-phosphate-independent receptor for lysosomal targeting of beta-GC.
Jovic et al. (2012) found that PI4KII-alpha (PI4K2A; 609763) and PI4KIII-beta (PI4KB; 602758), both of which synthesize phosphatidylinositol-4-phosphate (PtdIns4P), had distinct and sequential roles in the lysosomal delivery of beta-GC and LIMP2. Activity of PI4KIII-beta at the Golgi was required to drive exit of LIMP2 from the Golgi, whereas PI4KII-alpha at the trans-Golgi network regulated sorting of LIMP2 toward the late endosome/lysosome compartment. Knockdown or inhibition of PI3KIII-beta led to accumulation of LIMP2 at the Golgi compartment, and knockdown of either LIMP2 or PI4KII-alpha increased beta-GC secretion. Mutations in PI4KII-alpha that disrupted its association with AP3 (see AP3B1; 603401) disrupted lysosomal LIMP2 targeting.
Using a knockout screen in HeLa cells, Guo et al. (2022) identified SLC35B2 (610788), SCARB2, and B3GAT3 (606374) as host factors facilitating infection by enterovirus-71 (EV71). Knockout of SCARB2, SLC35B2, or B3GAT3 conferred strong protection against EV71 infection, whereas reintroduction of SCARB2, SLC35B2, or B3GAT3 restored infectivity of EV71 in knockout cells. Virus binding and internalization assays showed that SLC35B2 and B3GAT3 were essential for EV71 attachment and internalization in viral entry. SCARB2 played a relatively minor role in attachment and internalization, but it appeared to play a vital role in the viral uncoating step. Further analysis showed that host sulfation was critical for EV71 entry and that SLC35B2 could act as a vital modulator for host sulfation. Heparan sulfate played an essential role in EV71 infection, with the involvement of some tyrosine-sulfated proteins. In support, SCARB2 was found to be sulfated at multiple tyrosine residues, and its tyrosine sulfation was critical for EV71 infection.
Crystal Structure
Neculai et al. (2013) determined the crystal structure of LIMP2 and inferred, by homology modeling, the structure of SRBI (601040) and CD36 (173510). LIMP2 shows a helical bundle where beta-glucocerebrosidase (GBA; 606463) binds, and where ligands are most likely to bind to SRBI and CD36. Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule. Mutagenesis of SRBI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane. Neculai et al. (2013) provided evidence supporting a model whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SRBI and CD36.
Action myoclonus-renal failure syndrome (AMRF) is a form of autosomal recessive progressive myoclonic epilepsy (EPM4; 254900) that combines progressive myoclonus epilepsy associated with storage material in the brain and focal glomerulosclerosis, frequently with glomerular collapse. Berkovic et al. (2008) mapped AMRF to chromosome 4q13-q21 and by microarray expression analysis identified SCARB2, which encodes a lysosomal membrane protein, as the most likely candidate in the critical region. They found mutations in SCARB2 (see, e.g., 602257.0001-602257.0003) in all 3 families used for mapping and in 2 other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes.
In a Portuguese girl with progressive myoclonic epilepsy and nephrotic syndrome, Balreira et al. (2008) identified a homozygous mutation in the SCARB2 gene (W178X; 602257.0004).
Dibbens et al. (2009) identified homozygous or compound heterozygous mutations in the SCARB2 gene (see, e.g., 602257.0005-602257.0006) in 5 unrelated Italian patients with progressive myoclonic epilepsy who did not develop renal failure, even 10 to 15 years after onset. A comparison with other reported SCARB2 mutations did not reveal any apparent genotype/phenotype correlations.
Blanz et al. (2010) investigated the biochemical function of selected SCARB2 mutations in transfected cells. All 3 nonsense mutations led to retention of mutant protein in the endoplasmic reticulum (ER) but affected the binding to beta-glucocerebrosidase (GBA; 606463) differentially. Of the 3 nonsense mutations, only the Q288X mutation (602257.0003) was still able to bind to GBA as efficiently as wildtype SCARB2, whereas the W146SfsX16 (602257.0002) and W178X mutations lost their GBA-binding capacity almost completely. Disruption of either the helical arrangement or the amphiphatic nature of the coiled-coil domain (residues 145 to 288) abolished GBA binding, and a synthetic peptide comprising the coiled-coil domain of SCARB2 displayed pH-selective multimerization properties. In contrast to the reduced binding properties of the nonsense mutations within residues 145 to 288, the H363N mutation led to increased binding of GBA, indicating that the highly conserved his363 residue may modify the affinity of SCARB2 to its ligand. Blanz et al. (2010) concluded that both disruption of the coiled-coil structure and AMRF disease-causing mutations abolish GBA binding, indicating the importance of an intact coiled-coil structure for the interaction of SCARB2 and GBA.
Gamp et al. (2003) showed that Limp2-deficient mice have increased postnatal mortality associated with uni- or bilateral hydronephrosis caused by ureteropelvic junction obstruction. An accumulation of lysosomes in epithelial cells of the ureter as well as a disturbed apical expression of uroplakin (UPK1B; 602380) was observed, suggesting an impairment of membrane transport processes. Serious hearing impairment in Limp2-deficient animals was indicated by deficits in acoustic startle responses, in brainstem-evoked auditory potentials, and reduced endochondral potential. Limp2-deficient mice suffered from a massive decline of spiral ganglia in the cochlea concomitant with that of the inner and outer hair cells. These pathologic changes began at the age of 3 months and were thought to be secondary to degeneration of the stria vascularis. Limp2-deficient mice were also characterized by peripheral demyelinating neuropathy. Demyelinization was found to be associated with massive loss of peripheral myelin proteins and increased activity and expression of lysosomal proteins.
Reczek et al. (2007) found that Limp2 knockout in mice significantly reduced beta-GC content in liver and kidney, but had no effect on beta-GC mRNA. Limp2 -/- mice, but not wildtype mice, showed elevated serum beta-GC and increased GlcCer content in liver and lung, but not in kidney, spleen, and brain. Limp2 -/- mice did not show a robust Gaucher disease (see 230800)-like phenotype.
In a woman of Turkish Cypriot origin whose parents were first cousins, Berkovic et al. (2008) found that action myoclonus with renal failure (AMRF), or progressive myoclonic epilepsy-4 (EPM4; 254900) was related to homozygosity for a splice site mutation in the SCARB2 gene: 1239+1G-T. RT-PCR analysis showed that this mutation leads to retention of intron 10 and the insertion of 20 amino acids and premature termination of the protein at residue 433.
In an Australian woman whose ancestors came from Britain and who had no known consanguineous ancestry, Berkovic et al. (2008) found a frameshift mutation in exon 4 of the SCARB2 gene, 435_436insAG, as the cause of progressive myoclonic epilepsy-4 with renal failure (EPM4; 254900). The mutation resulted in frameshift predicted to truncate the protein to 160 amino acids (Trp146SerfsTer16). Berkovic et al. (2008) found the same mutation in a Canadian case without French Canadian ancestry reported by Badhwar et al. (2004). Parental DNA was not available for testing, so Berkovic et al. (2008) were unable to distinguish whether the mutation was homozygous or hemizygous for deletion of a segment of the chromosome 4 homolog that would normally bear the second pathogenic allele.
Berkovic et al. (2008) identified an SCARB2 mutation in 1 of the original families with action myoclonus with renal failure (EPM4; 254900) from Quebec reported by Badhwar et al. (2004). The 3 affected members were deceased, and no DNA was available for testing, but obligate carriers of this disorder had the mutation in exon 7 862C-T (gln288ter, Q288X), which was predicted to terminate the protein prematurely or lead to nonsense-mediated RNA decay of the transcript.
In a patient with progressive myoclonic epilepsy without renal failure, Dibbens et al. (2011) identified compound heterozygosity for 2 mutations in the SCARB2 gene: Q288X and a 1-bp insertion in intron 9 (1187+3insT; 602257.0007). The patient was originally reported by Costello et al. (2009). He had onset of myoclonic epilepsy at age 16 years, and became severely disabled, requiring a wheelchair by age 20. At age 27, he had intractable myoclonus, dysarthria, and dysphagia, but cognition remained intact and there was no evidence of renal failure. Electrophysiologic studies indicated a demyelinating peripheral neuropathy, with reduced sensory and motor action potentials and mildly decreased nerve conduction velocities.
In a Portuguese girl, born of consanguineous parents, with progressive myoclonic epilepsy and nephrotic syndrome (EPM4; 254900), Balreira et al. (2008) identified a homozygous 533G-A transition in exon 4 of the SCARB2 gene, resulting in a trp178-to-ter (W178X) substitution. At age 17 years, she developed rapidly progressive myoclonic epilepsy and nephropathy, and died at age 26 of pneumonia. The unaffected parents were heterozygous for the mutation. No SCARB2 protein was detected in patient fibroblasts. Patient fibroblasts showed 10% residual beta-glucosidase (GBA; 606463) activity and an abnormal glycosylation pattern, consistent with depletion of post-Golgi forms of the enzyme. However, leukocytes showed normal GBA activity. A sister was similarly affected and died at age 23 years. Balreira et al. (2008) noted that the human phenotype described in these patients does not correspond to the phenotype observed in Scarb2-null mouse models.
In an Italian man, born of consanguineous parents, with progressive myoclonic epilepsy-4 (EPM4; 254900), Dibbens et al. (2009) identified a homozygous A-to-C transversion (1116-2A-C) in intron 8 of the SCARB2 gene. The patient had onset of action myoclonus at age 14 years, followed by tonic-clonic seizures and ataxia at age 17. He became bedridden at age 19 and died at age 29. He never developed renal failure.
In an Italian woman, born of consanguineous parents, with progressive myoclonic epilepsy-4 (EPM4; 254900), Dibbens et al. (2009) identified a homozygous 1-bp deletion (1258delG) in exon 11 of the SCARB2 gene, predicted to result in premature termination. The patient had onset of action myoclonus and tonic-clonic seizures at age 23, followed by ataxia at age 24. She became wheelchair-bound at age 28 and died at age 33. She never developed renal failure.
For discussion of the 1187+3insT mutation that was found in compound heterozygous state in a patient with progressive myoclonic epilepsy-4 (EPM4; 254900) by Dibbens et al. (2011), see 602257.0003.
Badhwar, A., Berkovic, S. F., Dowling, J. P., Gonzales, M., Narayanan, S., Brodtmann, A., Berzen, L., Caviness, J., Trenkwalder, C., Winkelmann, J., Rivest, J., Lambert, M., Hernandez-Cossio, O., Carpenter, S., Andermann, F., Andermann, E. Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder. Brain 127: 2173-2182, 2004. [PubMed: 15364701] [Full Text: https://doi.org/10.1093/brain/awh263]
Balreira, A., Gaspar, P., Caiola, D., Chaves, J., Beirao, I., Lopes Lima, J., Azevedo, J. E., Sa Miranda, M. C. A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome. Hum. Molec. Genet. 17: 2238-2243, 2008. [PubMed: 18424452] [Full Text: https://doi.org/10.1093/hmg/ddn124]
Berkovic, S. F., Dibbens, L. M., Oshlack, A., Silver, J. D., Katerelos, M., Vears, D. F., Lullmann-Rauch, R., Blanz, J., Zhang, K. W., Stankovich, J., Kalnins, R. M., Dowling, J. P., and 14 others. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am. J. Hum. Genet. 82: 673-684, 2008. [PubMed: 18308289] [Full Text: https://doi.org/10.1016/j.ajhg.2007.12.019]
Blanz, J., Groth, J., Zachos, C., Wehling, C., Saftig, P., Schwake, M. Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase. Hum. Molec. Genet. 19: 563-572, 2010. [PubMed: 19933215] [Full Text: https://doi.org/10.1093/hmg/ddp523]
Calvo, D., Dopazo, J., Vega, M. A. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics 25: 100-106, 1995. [PubMed: 7539776] [Full Text: https://doi.org/10.1016/0888-7543(95)80114-2]
Costello, D. J., Chiappa, K. H., Siao, P. Progressive myoclonus epilepsy with demyelinating peripheral neuropathy and preserved intellect: a novel syndrome. Arch. Neurol. 66: 898-901, 2009. [PubMed: 19597094] [Full Text: https://doi.org/10.1001/archneurol.2009.131]
Dibbens, L. M., Karakis, I., Bayly, M. A., Costello, D. J., Cole, A. J., Berkovic, S. F. Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy. Arch. Neurol. 68: 812-813, 2011. [PubMed: 21670406] [Full Text: https://doi.org/10.1001/archneurol.2011.120]
Dibbens, L. M., Michelucci, R., Gambardella, A., Andermann, F., Rubboli, G., Bayly, M. A., Joensuu, T., Vears, D. F., Franceschetti, S., Canafoglia, L., Wallace, R., Bassuk, A. G., Power, D. A., Tassinari, C. A., Andermann, E., Lehesjoki A. E., Berkovic, S. F. SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure. Ann. Neurol. 66: 532-536, 2009. [PubMed: 19847901] [Full Text: https://doi.org/10.1002/ana.21765]
Fujita, H., Takata, Y., Kono, A., Tanaka, Y., Takahashi, T., Himeno, M., Kato, K. Isolation and sequencing of a cDNA clone encoding the 85 kDa human lysosomal sialoglycoprotein (hLGP85) in human metastatic pancreas islet tumor cells. Biochem. Biophys. Res. Commun. 184: 604-611, 1992. [PubMed: 1374238] [Full Text: https://doi.org/10.1016/0006-291x(92)90632-u]
Gamp, A.-C., Tanaka, Y., Lullmann-Rauch, R., Wittke, D., D'Hooge, R., De Deyn, P. P., Moser, T., Maier, H., Hartmann, D., Reiss, K., Illert, A.-L., von Figura, K., Saftig, P. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum. Molec. Genet. 12: 631-646, 2003. [PubMed: 12620969]
Guo, D., Yu, X., Wang, D., Li, Z., Zhou, Y., Xu, G., Yuan, B., Qin, Y., Chen, M. SLC35B2 acts in a dual role in the host sulfation required for EV71 infection. J. Virol. 96: e0204221, 2022. [PubMed: 35420441] [Full Text: https://doi.org/10.1128/jvi.02042-21]
Jovic, M., Kean, M. J., Szentpetery, Z., Polevoy, G., Gingras, A.-C., Brill, J. A., Balla, T. Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, beta-glucocerebrosidase. Molec. Biol. Cell 23: 1533-1545, 2012. [PubMed: 22337770] [Full Text: https://doi.org/10.1091/mbc.E11-06-0553]
Neculai, D., Schwake, M., Ravichandran, M., Zunke, F., Collins, R. F., Peters, J., Neculai, M., Plumb, J., Loppnau, P., Pizarro, J. C., Seitova, A., Trimble, W. S., Saftig, P., Grinstein, S., Dhe-Paganon, S. :Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504: 172-176, 2013. [PubMed: 24162852] [Full Text: https://doi.org/10.1038/nature12684]
Reczek, D., Schwake, M., Schroder, J., Hughes, H., Blanz, J., Jin, X., Brondyk, W., Van Patten, S., Edmunds, T., Saftig, P. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131: 770-783, 2007. [PubMed: 18022370] [Full Text: https://doi.org/10.1016/j.cell.2007.10.018]
Yamayoshi, S., Yamashita, Y., Li, J., Hanagata, N., Minowa, T., Takemura, T., Koike, S. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nature Med. 15: 798-801, 2009. [PubMed: 19543282] [Full Text: https://doi.org/10.1038/nm.1992]