Alternative titles; symbols
HGNC Approved Gene Symbol: LSR
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,249,002-35,267,964 (from NCBI)
LSR is a lipoprotein receptor primarily expressed in liver and activated by free fatty acids (Yen et al., 1999). LSR also acts as a cellular receptor for toxins produced by different species of Clostridium bacteria (Papatheodorou et al., 2012).
Using immunoprecipitation analysis, Yen et al. (1999) found that rat Lsr was expressed as a heterotrimer or tetramer consisting of 68-kD alpha and 56-kD beta subunits. They cloned 3 splice variants of rat Lsr. The 593-amino acid alpha subunit has N-terminal hydrophobic regions, followed by an NPGY motif, a dileucine lysosomal targeting signal, a transmembrane domain, a TNF-alpha receptor (see 191190) signature sequence, and a C-terminal cluster of positively and negatively charged residues that may provide an apolipoprotein (see 152200)-binding site. The 574-amino acid alpha-prime subunit lacks the dileucine motif, and the 525-amino acid beta subunit lacks the dileucine motif, the transmembrane domain, and the TNF-alpha receptor signature sequence. Northern blot analysis of rat tissues revealed expression of 2.1- and 1.9-kb transcripts primarily in liver. Western blot analysis showed expression of 66-kD and 58-kD proteins, consistent with the calculated molecular masses of Lsr-alpha and -beta, respectively.
By Northern blot analysis, Mesli et al. (2004) detected Lsr mRNA in all adult mouse tissues tested except muscle and heart. Lsr mRNA was most abundant in liver, lung, intestine, kidney, ovary, and testis. Immunofluorescence analysis demonstrated expression at the periphery of hepatocytes in adult liver and in fetal liver at embryonic day 12 (E12) and E15.
By location-based expression cloning in canine kidney cells using a human colon carcinoma cDNA library, Masuda et al. (2011) demonstrated that human LSR is a component of tricellular tight junctions. Human LSR contains 581 amino acids and has an extracellular immunoglobulin domain, followed by a transmembrane domain and a cytoplasmic domain. Immunofluorescence analysis confirmed that mouse Lsr localized to tricellular tight junctions in epithelial cells.
By database analysis, Hemmasi et al. (2015) identified 6 isoforms of human LSR that result from alternative splicing or differential translation initiation. The full-length protein contains 649 amino acids. The other isoforms lack small intracellular segments, small extracellular segments, and/or the transmembrane domain and cysteine-rich region. PCR of human colon carcinoma cell cDNA revealed an additional variant encoding an isoform lacking a large portion of the central region, including the transmembrane domain and cysteine-rich region.
Hemmasi et al. (2015) reported that the LSR gene contains 10 exons.
Gross (2015) mapped the LSR gene to chromosome 19q13.12 based on an alignment of the LSR sequence (GenBank BC047376) with the genomic sequence (GRCh38).
Using inhibition and transfection experiments, Yen et al. (1999) found by that rat Lsr bound low-density lipoprotein (LDL). Immunofluorescence microscopy demonstrated that LDL uptake required both Lsr-alpha and -beta and the presence of oleate.
Masuda et al. (2011) found that suppression of Lsr via RNA interference in mouse epithelial cells inhibited tight junction formation, epithelial barrier expression, and localization of tricellulin (MARVELD2; 610572) to tricellular contacts. Mutation analysis showed that the cytoplasmic domain of mouse Lsr recruited tricellulin to tricellular contacts.
Using recombinant Clostridium spiroforme toxin (CST) components, Papatheodorou et al. (2012) showed that CST entered human cell lines through LSR and that LSR was required for toxicity.
Clostridium difficile is a human enteric pathogen that causes antibiotic-induced diarrhea and pseudomembranous colitis. Hemmasi et al. (2015) showed that the C terminus of C. difficile transferase (CDT), which mediates the collapse of the cellular actin cytoskeleton and eventual cell death, interacted with the extracellular, Ig-like domain of human LSR with high affinity. CRISPR/Casp9-mediated truncation of LSR showed that the intracellular domains of LSR were not required for plasma membrane targeting and cellular uptake of CDT.
For discussion of a possible association between familial intrahepatic cholestasis (see 211600) and mutation in the LSR gene, see 616582.0001.
Mesli et al. (2004) observed embryonic lethality with reduced liver size in Lsr -/- mice between E12.5 and E15.5. Lsr +/- heterozygotes appeared normal. Mesli et al. (2004) concluded that the expression of LSR is critical for liver and embryonic development.
Stenger et al. (2012) demonstrated that heterozygous knockout mice had region-specific Lsr expression in the hippocampus, cerebellum Purkinje cells, the ependymal cell interface between brain parenchyma and cerebrospinal fluid, and the choroid plexus. Older heterozygous mice had longer latency in maze testing and were found to have membrane cholesterol content accumulation accompanied by significantly altered distribution of Lsr in the membrane as well as decreased intracellular lipid droplets in the cerebellum and hippocampus compared to control littermates and young heterozygous mice. The authors argued that the data show the importance of LSR in brain cholesterol distribution and maintenance of cognitive functions during aging.
This variant is classified as a variant of unknown significance because its contribution to familial intrahepatic cholestasis (see 211600) has not been confirmed.
By autozygosity mapping followed by exome sequencing in a boy (family 6) with cholestasis, Maddirevula et al. (2019) identified homozygosity for a c.704A-G transition (c.704A-G, NM_001260489.1) in the LSR gene, resulting in a glu235-to-gly (E235G) substitution. The mutation segregated with available members in the family and was not present in the gnomAD database or in an in-house database. The patient presented at 4 months of age with high total serum bile acids, total/direct bilirubin, ALT, AST, ALP, and normal GGT. He had mildly impaired intellectual development (IQ, 70-77), speech delay, severely impaired fine motor coordination, and short stature. At age 1 year, his liver biopsy showed a morphology consistent with paucity of the intrahepatic bile duct. Hepatocytes showed giant cell transformation with feathery degeneration associated with intrahepatic and canalicular cholestasis. Severe itching was difficult to control with medication.
Gross, M. B. Personal Communication. Baltimore, Md. 9/30/2015.
Hemmasi, S., Czulkies, B. A., Schorch, B., Veit, A., Aktories, K., Papatheodorou, P. Interaction of the Clostridium difficile binary toxin CDT and its host cell receptor, lipolysis-stimulated lipoprotein receptor (LSR). J. Biol. Chem. 290: 14031-14044, 2015. [PubMed: 25882847] [Full Text: https://doi.org/10.1074/jbc.M115.650523]
Maddirevula, S., Alhebbi, H., Alqahtani, A., Algoufi, T., Alsaif, H. S., Ibrahim, N., Abdulwahab, F., Barr, M., Alzaidan, H., Almehaideb, A., AlSasi, O., Alhashem, A., Al-Hussaini, H., Wali, S., Alkuraya, F. S. Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet. Med. 21: 1164-1172, 2019. [PubMed: 30250217] [Full Text: https://doi.org/10.1038/s41436-018-0288-x]
Masuda, S., Oda, Y., Sasaki, H., Ikenouchi, J., Higashi, T., Akashi, M., Nishi, E., Furuse, M. LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 124: 548-555, 2011. [PubMed: 21245199] [Full Text: https://doi.org/10.1242/jcs.072058]
Mesli, S., Javorschi, S., Berard, A. M., Landry, M., Priddle, H., Kivlichan, D., Smith, A. J., Yen, F. T., Bihain, B. E., Darmon, M. Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSR -/- embryos at 12.5 to 14.5 days of gestation. Europ. J. Biochem. 271: 3103-3114, 2004. [PubMed: 15265030] [Full Text: https://doi.org/10.1111/j.1432-1033.2004.04223.x]
Papatheodorou, P., Wilczek, C., Nolke, T., Guttenberg, G., Hornuss, D., Schwan, C., Aktories, K. Identification of the cellular receptor of Clostridium spiroforme toxin. Infect. Immun. 80: 1418-1423, 2012. [PubMed: 22252869] [Full Text: https://doi.org/10.1128/IAI.06378-11]
Stenger, C., Pincon, A., Hanse, M., Royer, L., Comte, A., Koziel, V., Olivier, J.-L., Pillot, T., Yen, F. T. Brain region-specific immunolocalization of the lipolysis-stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR+/- mice. J. Neurochem. 123: 467-476, 2012. [PubMed: 22909011] [Full Text: https://doi.org/10.1111/j.1471-4159.2012.07922.x]
Yen, F. T., Masson, M., Clossias-Besnard, N., Andre, P., Grosset, J.-M., Bougueleret, L., Dumas, J.-B., Guerassimenko, O., Bihain, B. E. Molecular cloning of a lipolysis-stimulated remnant receptor expressed in rat liver. J. Biol. Chem. 274: 13390-13398, 1999. [PubMed: 10224102] [Full Text: https://doi.org/10.1074/jbc.274.19.13390]