* 153622

MACROPHAGE SCAVENGER RECEPTOR; MSR1


Alternative titles; symbols

SCAVENGER RECEPTOR CLASS A, MEMBER 1; SCARA1
SRA


HGNC Approved Gene Symbol: MSR1

Cytogenetic location: 8p22     Genomic coordinates (GRCh38): 8:16,107,881-16,192,651 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8p22 Barrett esophagus/esophageal adenocarcinoma 614266 3

TEXT

Cloning and Expression

Macrophage scavenger receptors mediate the binding, internalization, and processing of a wide range of negatively charged macromolecules (Emi et al., 1993). The macrophage scavenger receptors are trimeric membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis. Functional MSRs are trimers of 2 C-terminally different subunits generated by alternative splicing. The subunits contain 6 functional domains. Matsumoto et al. (1990) cloned 2 types of cDNAs for human macrophage scavenger receptors from a cDNA library derived from the phorbol ester-treated human monocyte cell line THP-1. The type I and type II receptors encoded by these cDNAs were homologous to their previously characterized bovine counterparts.


Gene Function

Seimon et al. (2006) found that Sra ligands failed to trigger apoptosis in endoplasmic reticulum (ER)-stressed macrophages from Tlr4 (603030) -/- mice. Sra ligands could stimulate Sra -/- ER-stressed macrophages through Tlr4 to activate Nfkb (see 164011) and Jnk (see JNK1; 601158). Cytoplasmic calcium was required for Tlr4-induced Jnk activation and apoptosis in ER-stressed macrophages. Apoptosis also required Sra-dependent suppression of Irf3 (603734)-Ifnb (147640) signaling, which is involved in cell survival. Seimon et al. (2006) concluded that combinatorial signaling between TLR4 and SRA results in a functional outcome, macrophage apoptosis, that does not occur with either receptor alone.


Gene Structure

Emi et al. (1993) determined that the human MSR1 gene consists of 11 exons. The 2 types of mRNAs are generated by alternative splicing from exon 8 to either exon 9 (type II) or to exons 10 and 11 (type I). Exon 1 encodes the 5-prime untranslated region followed by a 12-kb intron which separates the transcription initiation and the translation initiation sites. Exon 2 encodes a cytoplasmic domain; exon 3, a transmembrane domain; exons 4 and 5, an alpha-helical coiled-coil; and exons 6-8, a collagen-like domain.


Mapping

By study of somatic cell hybrids, Matsumoto et al. (1990) determined that the human macrophage scavenger receptor gene is located on chromosome 8. Emi et al. (1993) cloned an 80-kb human MSR gene and assigned it to 8p22 by fluorescence in situ hybridization and by genetic linkage using 3 common RFLPs. In linkage studies, the MSR locus appeared to lie approximately 11 cM distal to the LPL locus (238600), which is also in 8p22, with the marker D8S21 lying between the 2 loci.


Molecular Genetics

Prostate Cancer

Deletions on 8p23-p22 in prostate cancer cells (Latil and Lidereau, 1998) and linkage studies in families affected with hereditary prostate cancer (176807) (Xu et al., 2001) have implicated this region in the development of prostate cancer. The MSR1 gene is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. In studies of families affected with hereditary prostate cancer, Xu et al. (2002) identified 6 missense mutations and 1 nonsense mutation in the MSR1 gene. A family-based linkage and association test indicated that these mutations cosegregate with prostate cancer (p = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with nonhereditary prostate cancer as compared with 0.8% of unaffected men (p = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (p = 0.01). These results showed that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Xu et al. (2003) compared the frequency of 5 common MSR1 variants in 301 patients who did not meet the criteria for hereditary prostate cancer who underwent prostate cancer therapy and in 250 control subjects who participated in prostate cancer screening programs and had normal digital rectal examination and prostate-specific antigen (PSA; 176820) levels. Significantly different allele frequencies between case subjects and controls were observed for each of the 5 variants. Because the haplotype associated with increased risk for prostate cancer did not harbor any rare mutations, the observed association of common variants and prostate cancer risk appeared independent of the effect of the rare mutations. The results suggested that MSR1 may play an important role in prostate carcinogenesis.

Miller et al. (2003) evaluated further the association of germline mutations and common MSR1 sequence variants with prostate cancer risk in a case-control study of a community-based sample of 134 African American men with prostate cancer and 340 unaffected controls. In this sample, the asp174-to-tyr missense change (153622.0002) was identified nearly twice as frequently in men with prostate cancer (6.8%) compared with unaffected controls (3.6%; p = 0.14). Moreover, significantly different allele frequencies between cases and controls were observed for one of the sequence variants.

Wang et al. (2003) screened the MSR1 gene for germline mutations in individuals with familial prostate cancer and tested gene variants for associations in both sporadic and familial prostate cancer. Their results did not support MSR1 as a risk factor for prostate cancer.

Maier et al. (2005) conducted a genomewide linkage search in 139 German prostate cancer families and found the most evident linkage at 8p22 in the region of the MSR1 gene. Several other loci worthy of further study were identified.

Prompted by reasonable support for linkage of familial prostate cancer to 8p22, Maier et al. (2006) sought to determine the mutation spectrum of MSR1 in their family sample. Screening of 139 probands representing 139 prostate cancer families revealed 15 novel and a total of 20 sequence variants within the 10 coding exons and their intronic proximities. Aside from the 877C-T mutation (R293X; 153622.0001) present in 2 of their families, they identified a second nonsense mutation and a splice site mutation that resulted in mRNA instability, each in a single pedigree. Five other novel missense alleles were found. Of the 8 variants that affected the encoded protein (splice site, nonsense, and missense), only R293X and a known polymorphism were additionally present at remarkable frequencies in further samples of sporadic prostate cancer and in controls. Of note, carriers of R293X were equally frequent in 367 sporadic prostate cancer cases (1.9%) and in 197 controls (2.0%). Maier et al. (2006) stated that, to their knowledge, this study was the first to demonstrate further loss of function variants of MSR1 apart from R293X. Nevertheless, they concluded that the low frequencies of deleterious alleles, in addition to an apparently moderate penetrance, did not support MSR1 as a major susceptibility gene in this family sample.

Barrett Esophagus and/or Esophageal Adenocarcinoma

Orloff et al. (2011) identified a germline R293X substitution (153622.0001) in the MSR1 gene in 8 (6.9%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The findings were replicated in an independent study of 58 patients, of whom 2 (3.4%) had the R293X mutation. Western blot analysis showed variable decreases in the MSR1 protein in 3 of 5 cases with the mutation, and all 5 patients had increased nuclear expression of cyclin D1 (CCND1; 168461) compared to controls. In addition, a germline leu254-to-val (L254V; 153622.0003) substitution was found in 2 patients (1.7%). The findings suggested a link between inflammation and the cell cycle and the development of Barrett esophagus and/or esophageal cancer. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.


Animal Model

Ricci et al. (2004) showed that atherosclerosis-prone ApoE (107741) null mice simultaneously lacking Jnk2 (602896) (ApoE -/- Jnk2 -/- mice), but not ApoE -/- Jnk1 -/- mice, developed less atherosclerosis than do ApoE null mice. Pharmacologic inhibition of Jnk activity efficiently reduced plaque formation. Macrophages lacking Jnk2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SRA, also known as MSR1), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of Jnk2 was sufficient to decrease atherogenesis. Thus, Ricci et al. (2004) concluded that JNK2-dependent phosphorylation of SRA promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.


ALLELIC VARIANTS ( 3 Selected Examples):

.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSR1, ARG293TER
  
RCV000015431...

This variant, formerly titled PROSTATE CANCER, has been reclassified based on the report of Wang et al. (2003).

In 6 different families, all of European descent, with hereditary prostate cancer (176807), Xu et al. (2002) found a nonsense mutation, arg293 to ter (R293X), in the MSR1 gene.

Wang et al. (2003) found no statistical difference between prostate cancer cases with the R293X mutation and controls for either familial or sporadic cancer.

Orloff et al. (2011) identified a germline 877C-T transition in the MSR1 gene, resulting in an arg293-to-ter (R293X) substitution in a highly conserved collagen-like domain, in 8 (6.9%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The findings were replicated in an independent study of 58 patients, of whom 2 (3.4%) had the R293X mutation. The mutation was not found in 139 controls. Western blot analysis showed variable decreases in the MSR1 protein in 3 of 5 cases with the mutation, and all 5 patients had increased nuclear expression of cyclin D1 (CCND1; 168461) compared to controls. The findings suggested a link between inflammation and the cell cycle and the development of Barrett esophagus and/or esophageal cancer. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.


.0002 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSR1, ASP174TYR
  
RCV000015432

This variant, formerly titled PROSTATE CANCER, has been reclassified based on a review of the gnomAD database by Hamosh (2018).

In 4 different families, all African American, with hereditary prostate cancer (176807), Xu et al. (2002) found an asp174-to-tyr (D174Y) change in the MSR1 gene.

Hamosh (2018) found the D174Y variant in 537 of 24,032 alleles and in 4 homozygotes in the African population, with an allele frequency of 0.02235, in the gnomAD database (March 26, 2018).


.0003 BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMA

MSR1, LEU254VAL
  
RCV000022646

Orloff et al. (2011) identified a germline 760C-G transversion in exon 5 of the MSR1 gene, resulting in a leu254-to-val (L254V) substitution in 2 (1.7%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 139 controls. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant sibs pairs with the disorders and 11 discordant sib pairs.


REFERENCES

  1. Emi, M., Asaoka, H., Matsumoto, A., Itakura, H., Kurihara, Y., Wada, Y., Kanamori, H., Yazaki, Y., Takahashi, E., Lepert, M., Lalouel, J.-M., Kodama, T., Mukai, T. Structure, organization, and chromosomal mapping of the human macrophage scavenger receptor gene. J. Biol. Chem. 268: 2120-2125, 1993. [PubMed: 8093617, related citations]

  2. Hamosh, A. Personal Communication. Baltimore, Md. 3/26/2018.

  3. Latil, A., Lidereau, R. Genetic aspects of prostate cancer. Virchows Arch. 432: 389-406, 1998. [PubMed: 9645438, related citations] [Full Text]

  4. Maier, C., Herkommer, K., Hoegel, J., Vogel, W., Paiss, T. A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Europ. J. Hum. Genet. 13: 352-360, 2005. [PubMed: 15536476, related citations] [Full Text]

  5. Maier, C., Vesovic, Z., Bachmann, N., Herkommer, K., Braun, A. K., Surowy, H. M., Assum, G., Paiss, T., Vogel, W. Germline mutations of the MSR1 gene in prostate cancer families from Germany. Hum. Mutat. 27: 98-102, 2006. [PubMed: 16287155, related citations] [Full Text]

  6. Matsumoto, A., Naito, M., Itakura, H., Ikemoto, S., Asaoka, H., Hayakawa, I., Kanamori, H., Aburatani, H., Takaku, F., Suzuki, H., Kobari, Y., Miyai, T., Takahashi, K., Cohen, E. H., Wydro, R., Housman, D. E., Kodama, T. Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions. Proc. Nat. Acad. Sci. 87: 9133-9137, 1990. [PubMed: 2251254, related citations] [Full Text]

  7. Miller, D. C., Zheng, S. L., Dunn, R. L., Sarma, A. V., Montie, J. E., Lange, E. M., Meyers, D. A., Xu, J., Cooney, K. A. Germ-line mutations of the macrophage scavenger receptor 1 gene: association with prostate cancer risk in African-American men. Cancer Res. 63: 3486-3489, 2003. [PubMed: 12839931, related citations]

  8. Orloff, M., Peterson, C., He, X., Ganapathi, S., Heald, B., Yang, Y., Bebek, G., Romigh, T., Song, J. H., Wu, W., David, S., Cheng, Y., Meltzer, S. J., Eng, C. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 306: 410-419, 2011. [PubMed: 21791690, images, related citations] [Full Text]

  9. Ricci, R., Sumara, G., Sumara, I., Rozenberg, I., Kurrer, M., Akhmedov, A., Hersberger, M., Eriksson, U., Eberli, F. R., Becher, B., Boren, J., Chen, M., Cybulsky, M. I., Moore, K. J., Freeman, M. W., Wagner, E. F., Matter, C. M., Luscher, T. F. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 306: 1558-1561, 2004. [PubMed: 15567863, related citations] [Full Text]

  10. Seimon, T. A., Obstfeld, A., Moore, K. J., Golenbock, D. T., Tabas, I. Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc. Nat. Acad. Sci. 103: 19794-19799, 2006. [PubMed: 17167049, images, related citations] [Full Text]

  11. Wang, L., McDonnell, S. K., Cunningham, J. M., Hebbring, S., Jacobsen, S. J., Cerhan, J. R., Slager, S. L., Blute, M. L., Schaid, D. J., Thibodeau, S. N. No association of germline alteration of MSR1 with prostate cancer risk. Nature Genet. 35: 128-129, 2003. [PubMed: 12958598, related citations] [Full Text]

  12. Xu, J., Zheng, S. L., Hawkins, G. A., Faith, D. A., Kelly, B., Isaacs, S. D., Wiley, K. E., Chang, B., Ewing, C. M., Bujnovszky, P., Carpten, J. D., Bleecker, E. R., Walsh, P. C., Trent, J. M., Meyers, D. A., Isaacs, W. B. Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am. J. Hum. Genet. 69: 341-350, 2001. [PubMed: 11443539, related citations] [Full Text]

  13. Xu, J., Zheng, S. L., Komiya, A., Mychaleckyj, J. C., Isaacs, S. D., Chang, B., Turner, A. R., Ewing, C. M., Wiley, K. E., Hawkins, G. A., Bleecker, E. R., Walsh, P. C., Meyers, D. A., Isaacs, W. B. Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am. J. Hum. Genet. 72: 208-212, 2003. [PubMed: 12471593, related citations] [Full Text]

  14. Xu, J., Zheng, S. L., Komiya, A., Mychaleckyj, J. C., Isaacs, S. D., Hu, J. J., Sterling, D., Lange, E. M., Hawkins, G. A., Turner, A., Ewing, C. M., Faith, D. A., and 19 others. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nature Genet. 32: 321-325, 2002. [PubMed: 12244320, related citations] [Full Text]


Ada Hamosh - updated : 12/05/2016
Cassandra L. Kniffin - updated : 9/21/2011
Paul J. Converse - updated : 4/26/2007
Victor A. McKusick - updated : 1/20/2006
Victor A. McKusick - updated : 4/4/2005
Ada Hamosh - updated : 12/10/2004
Victor A. McKusick - updated : 9/23/2003
Victor A. McKusick - updated : 9/12/2003
Victor A. McKusick - updated : 1/22/2003
Victor A. McKusick - updated : 9/24/2002
Creation Date:
Victor A. McKusick : 1/3/1991
carol : 03/27/2018
alopez : 12/05/2016
carol : 08/18/2016
carol : 10/04/2011
ckniffin : 10/4/2011
carol : 10/4/2011
carol : 10/4/2011
ckniffin : 10/4/2011
ckniffin : 9/21/2011
carol : 8/6/2007
mgross : 4/26/2007
mgross : 4/26/2007
alopez : 2/15/2006
terry : 1/20/2006
wwang : 4/8/2005
terry : 4/4/2005
alopez : 12/14/2004
alopez : 12/14/2004
alopez : 12/14/2004
alopez : 12/14/2004
terry : 12/10/2004
terry : 5/20/2004
alopez : 2/17/2004
tkritzer : 9/24/2003
tkritzer : 9/23/2003
cwells : 9/12/2003
cwells : 9/12/2003
tkritzer : 1/31/2003
tkritzer : 1/24/2003
terry : 1/22/2003
alopez : 9/24/2002
alopez : 9/24/2002
carol : 3/20/1993
carol : 3/19/1993
supermim : 3/16/1992
carol : 9/3/1991
carol : 1/3/1991

* 153622

MACROPHAGE SCAVENGER RECEPTOR; MSR1


Alternative titles; symbols

SCAVENGER RECEPTOR CLASS A, MEMBER 1; SCARA1
SRA


HGNC Approved Gene Symbol: MSR1

Cytogenetic location: 8p22     Genomic coordinates (GRCh38): 8:16,107,881-16,192,651 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
8p22 Barrett esophagus/esophageal adenocarcinoma 614266 3

TEXT

Cloning and Expression

Macrophage scavenger receptors mediate the binding, internalization, and processing of a wide range of negatively charged macromolecules (Emi et al., 1993). The macrophage scavenger receptors are trimeric membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis. Functional MSRs are trimers of 2 C-terminally different subunits generated by alternative splicing. The subunits contain 6 functional domains. Matsumoto et al. (1990) cloned 2 types of cDNAs for human macrophage scavenger receptors from a cDNA library derived from the phorbol ester-treated human monocyte cell line THP-1. The type I and type II receptors encoded by these cDNAs were homologous to their previously characterized bovine counterparts.


Gene Function

Seimon et al. (2006) found that Sra ligands failed to trigger apoptosis in endoplasmic reticulum (ER)-stressed macrophages from Tlr4 (603030) -/- mice. Sra ligands could stimulate Sra -/- ER-stressed macrophages through Tlr4 to activate Nfkb (see 164011) and Jnk (see JNK1; 601158). Cytoplasmic calcium was required for Tlr4-induced Jnk activation and apoptosis in ER-stressed macrophages. Apoptosis also required Sra-dependent suppression of Irf3 (603734)-Ifnb (147640) signaling, which is involved in cell survival. Seimon et al. (2006) concluded that combinatorial signaling between TLR4 and SRA results in a functional outcome, macrophage apoptosis, that does not occur with either receptor alone.


Gene Structure

Emi et al. (1993) determined that the human MSR1 gene consists of 11 exons. The 2 types of mRNAs are generated by alternative splicing from exon 8 to either exon 9 (type II) or to exons 10 and 11 (type I). Exon 1 encodes the 5-prime untranslated region followed by a 12-kb intron which separates the transcription initiation and the translation initiation sites. Exon 2 encodes a cytoplasmic domain; exon 3, a transmembrane domain; exons 4 and 5, an alpha-helical coiled-coil; and exons 6-8, a collagen-like domain.


Mapping

By study of somatic cell hybrids, Matsumoto et al. (1990) determined that the human macrophage scavenger receptor gene is located on chromosome 8. Emi et al. (1993) cloned an 80-kb human MSR gene and assigned it to 8p22 by fluorescence in situ hybridization and by genetic linkage using 3 common RFLPs. In linkage studies, the MSR locus appeared to lie approximately 11 cM distal to the LPL locus (238600), which is also in 8p22, with the marker D8S21 lying between the 2 loci.


Molecular Genetics

Prostate Cancer

Deletions on 8p23-p22 in prostate cancer cells (Latil and Lidereau, 1998) and linkage studies in families affected with hereditary prostate cancer (176807) (Xu et al., 2001) have implicated this region in the development of prostate cancer. The MSR1 gene is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. In studies of families affected with hereditary prostate cancer, Xu et al. (2002) identified 6 missense mutations and 1 nonsense mutation in the MSR1 gene. A family-based linkage and association test indicated that these mutations cosegregate with prostate cancer (p = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with nonhereditary prostate cancer as compared with 0.8% of unaffected men (p = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (p = 0.01). These results showed that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Xu et al. (2003) compared the frequency of 5 common MSR1 variants in 301 patients who did not meet the criteria for hereditary prostate cancer who underwent prostate cancer therapy and in 250 control subjects who participated in prostate cancer screening programs and had normal digital rectal examination and prostate-specific antigen (PSA; 176820) levels. Significantly different allele frequencies between case subjects and controls were observed for each of the 5 variants. Because the haplotype associated with increased risk for prostate cancer did not harbor any rare mutations, the observed association of common variants and prostate cancer risk appeared independent of the effect of the rare mutations. The results suggested that MSR1 may play an important role in prostate carcinogenesis.

Miller et al. (2003) evaluated further the association of germline mutations and common MSR1 sequence variants with prostate cancer risk in a case-control study of a community-based sample of 134 African American men with prostate cancer and 340 unaffected controls. In this sample, the asp174-to-tyr missense change (153622.0002) was identified nearly twice as frequently in men with prostate cancer (6.8%) compared with unaffected controls (3.6%; p = 0.14). Moreover, significantly different allele frequencies between cases and controls were observed for one of the sequence variants.

Wang et al. (2003) screened the MSR1 gene for germline mutations in individuals with familial prostate cancer and tested gene variants for associations in both sporadic and familial prostate cancer. Their results did not support MSR1 as a risk factor for prostate cancer.

Maier et al. (2005) conducted a genomewide linkage search in 139 German prostate cancer families and found the most evident linkage at 8p22 in the region of the MSR1 gene. Several other loci worthy of further study were identified.

Prompted by reasonable support for linkage of familial prostate cancer to 8p22, Maier et al. (2006) sought to determine the mutation spectrum of MSR1 in their family sample. Screening of 139 probands representing 139 prostate cancer families revealed 15 novel and a total of 20 sequence variants within the 10 coding exons and their intronic proximities. Aside from the 877C-T mutation (R293X; 153622.0001) present in 2 of their families, they identified a second nonsense mutation and a splice site mutation that resulted in mRNA instability, each in a single pedigree. Five other novel missense alleles were found. Of the 8 variants that affected the encoded protein (splice site, nonsense, and missense), only R293X and a known polymorphism were additionally present at remarkable frequencies in further samples of sporadic prostate cancer and in controls. Of note, carriers of R293X were equally frequent in 367 sporadic prostate cancer cases (1.9%) and in 197 controls (2.0%). Maier et al. (2006) stated that, to their knowledge, this study was the first to demonstrate further loss of function variants of MSR1 apart from R293X. Nevertheless, they concluded that the low frequencies of deleterious alleles, in addition to an apparently moderate penetrance, did not support MSR1 as a major susceptibility gene in this family sample.

Barrett Esophagus and/or Esophageal Adenocarcinoma

Orloff et al. (2011) identified a germline R293X substitution (153622.0001) in the MSR1 gene in 8 (6.9%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The findings were replicated in an independent study of 58 patients, of whom 2 (3.4%) had the R293X mutation. Western blot analysis showed variable decreases in the MSR1 protein in 3 of 5 cases with the mutation, and all 5 patients had increased nuclear expression of cyclin D1 (CCND1; 168461) compared to controls. In addition, a germline leu254-to-val (L254V; 153622.0003) substitution was found in 2 patients (1.7%). The findings suggested a link between inflammation and the cell cycle and the development of Barrett esophagus and/or esophageal cancer. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.


Animal Model

Ricci et al. (2004) showed that atherosclerosis-prone ApoE (107741) null mice simultaneously lacking Jnk2 (602896) (ApoE -/- Jnk2 -/- mice), but not ApoE -/- Jnk1 -/- mice, developed less atherosclerosis than do ApoE null mice. Pharmacologic inhibition of Jnk activity efficiently reduced plaque formation. Macrophages lacking Jnk2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SRA, also known as MSR1), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of Jnk2 was sufficient to decrease atherogenesis. Thus, Ricci et al. (2004) concluded that JNK2-dependent phosphorylation of SRA promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.


ALLELIC VARIANTS 3 Selected Examples):

.0001   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSR1, ARG293TER
SNP: rs41341748, gnomAD: rs41341748, ClinVar: RCV000015431, RCV000210798, RCV000481066, RCV001258304, RCV003133117, RCV003964803

This variant, formerly titled PROSTATE CANCER, has been reclassified based on the report of Wang et al. (2003).

In 6 different families, all of European descent, with hereditary prostate cancer (176807), Xu et al. (2002) found a nonsense mutation, arg293 to ter (R293X), in the MSR1 gene.

Wang et al. (2003) found no statistical difference between prostate cancer cases with the R293X mutation and controls for either familial or sporadic cancer.

Orloff et al. (2011) identified a germline 877C-T transition in the MSR1 gene, resulting in an arg293-to-ter (R293X) substitution in a highly conserved collagen-like domain, in 8 (6.9%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The findings were replicated in an independent study of 58 patients, of whom 2 (3.4%) had the R293X mutation. The mutation was not found in 139 controls. Western blot analysis showed variable decreases in the MSR1 protein in 3 of 5 cases with the mutation, and all 5 patients had increased nuclear expression of cyclin D1 (CCND1; 168461) compared to controls. The findings suggested a link between inflammation and the cell cycle and the development of Barrett esophagus and/or esophageal cancer. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders.


.0002   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

MSR1, ASP174TYR
SNP: rs72552387, gnomAD: rs72552387, ClinVar: RCV000015432

This variant, formerly titled PROSTATE CANCER, has been reclassified based on a review of the gnomAD database by Hamosh (2018).

In 4 different families, all African American, with hereditary prostate cancer (176807), Xu et al. (2002) found an asp174-to-tyr (D174Y) change in the MSR1 gene.

Hamosh (2018) found the D174Y variant in 537 of 24,032 alleles and in 4 homozygotes in the African population, with an allele frequency of 0.02235, in the gnomAD database (March 26, 2018).


.0003   BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMA

MSR1, LEU254VAL
SNP: rs387906645, gnomAD: rs387906645, ClinVar: RCV000022646

Orloff et al. (2011) identified a germline 760C-G transversion in exon 5 of the MSR1 gene, resulting in a leu254-to-val (L254V) substitution in 2 (1.7%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 139 controls. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant sibs pairs with the disorders and 11 discordant sib pairs.


REFERENCES

  1. Emi, M., Asaoka, H., Matsumoto, A., Itakura, H., Kurihara, Y., Wada, Y., Kanamori, H., Yazaki, Y., Takahashi, E., Lepert, M., Lalouel, J.-M., Kodama, T., Mukai, T. Structure, organization, and chromosomal mapping of the human macrophage scavenger receptor gene. J. Biol. Chem. 268: 2120-2125, 1993. [PubMed: 8093617]

  2. Hamosh, A. Personal Communication. Baltimore, Md. 3/26/2018.

  3. Latil, A., Lidereau, R. Genetic aspects of prostate cancer. Virchows Arch. 432: 389-406, 1998. [PubMed: 9645438] [Full Text: https://doi.org/10.1007/s004280050183]

  4. Maier, C., Herkommer, K., Hoegel, J., Vogel, W., Paiss, T. A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany. Europ. J. Hum. Genet. 13: 352-360, 2005. [PubMed: 15536476] [Full Text: https://doi.org/10.1038/sj.ejhg.5201333]

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Contributors:
Ada Hamosh - updated : 12/05/2016
Cassandra L. Kniffin - updated : 9/21/2011
Paul J. Converse - updated : 4/26/2007
Victor A. McKusick - updated : 1/20/2006
Victor A. McKusick - updated : 4/4/2005
Ada Hamosh - updated : 12/10/2004
Victor A. McKusick - updated : 9/23/2003
Victor A. McKusick - updated : 9/12/2003
Victor A. McKusick - updated : 1/22/2003
Victor A. McKusick - updated : 9/24/2002

Creation Date:
Victor A. McKusick : 1/3/1991

Edit History:
carol : 03/27/2018
alopez : 12/05/2016
carol : 08/18/2016
carol : 10/04/2011
ckniffin : 10/4/2011
carol : 10/4/2011
carol : 10/4/2011
ckniffin : 10/4/2011
ckniffin : 9/21/2011
carol : 8/6/2007
mgross : 4/26/2007
mgross : 4/26/2007
alopez : 2/15/2006
terry : 1/20/2006
wwang : 4/8/2005
terry : 4/4/2005
alopez : 12/14/2004
alopez : 12/14/2004
alopez : 12/14/2004
alopez : 12/14/2004
terry : 12/10/2004
terry : 5/20/2004
alopez : 2/17/2004
tkritzer : 9/24/2003
tkritzer : 9/23/2003
cwells : 9/12/2003
cwells : 9/12/2003
tkritzer : 1/31/2003
tkritzer : 1/24/2003
terry : 1/22/2003
alopez : 9/24/2002
alopez : 9/24/2002
carol : 3/20/1993
carol : 3/19/1993
supermim : 3/16/1992
carol : 9/3/1991
carol : 1/3/1991