Alternative titles; symbols
HGNC Approved Gene Symbol: SAA1
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:18,266,264-18,269,967 (from NCBI)
The serum amyloid A (SAA) protein is an acute phase apolipoprotein reactant produced mainly by hepatocytes and under regulation of inflammatory cytokines. The SAA cleavage product, designated amyloid protein A (AA), is deposited systemically as amyloid in vital organs including the liver, spleen, and kidneys in patients with chronic inflammatory diseases (summary by Lundmark et al., 2002).
The serum amyloid A proteins are chemically and antigenically related to the A proteins of secondary amyloidosis and are associated with the plasma high-density lipoproteins. Bausserman et al. (1980) isolated 6 polymorphic forms of SAA that have an identical molecular weight and COOH-terminal sequence but different electrophoretic mobilities at alkaline pH. In further studies of 4 of the 6, Bausserman et al. (1982) demonstrated differences in the NH2-terminal residues of certain ones and interpreted this as indicating that some of the SAA polymorphs are products of different genes.
Serum amyloid A is the proteolytic cleavage product of an acute phase reactant. Upon cleavage from the parent product, called SAAL (L = liver), AA can aggregate into insoluble antiparallel beta-pleated sheet fibrils which cause the systemic complications known as amyloidosis. Sack (1983) cloned the human genes for SAAL. Kluve-Beckerman et al. (1986) cloned human SAA-specific cDNAs and determined their nucleotide sequence.
An SAA gene was assigned to mouse chromosome 7 by study of recombinant inbred strains (Taylor and Rowe, 1984). By means of a cDNA probe for Southern analysis of DNA from human/mouse somatic cell hybrids, Kluve-Beckerman et al. (1986) assigned the SAA gene to 11pter-p11. The distal part of 11p has homology of synteny with mouse 7, whereas the proximal part has homology with mouse 2. The most proximal locus homologous on mouse 7 is LDHA (150000) which is located on 11p12.08-p12.03. The most distal locus homologous on mouse 2 is acid phosphatase-1 (171650) at 11p12-p11.
Sack et al. (1989) confirmed the assignment of the SAA gene to the short arm of chromosome 11 and concluded that the SAA gene family comprises at least 3 members in the haploid human genome. Strachan et al. (1989) presented evidence for 2 SAA loci. See SAA2 (104751). Stevens et al. (1993) indicated that cDNA probe pSAA82 detects 3 serum amyloid A loci on chromosome 11p. SAA1 and SAA2 have 90% nucleotide identity in exon and intron sequences (Betts et al., 1991), whereas SAA3 has an average of 70% identity with SAA1 and SAA2 (Kluve-Beckerman et al., 1991). SAA3 is a pseudogene, while SAA4 (104752) is a low-level, constitutively expressed gene.
Sellar et al. (1994) used a combination of physical and genetic mapping techniques to demonstrate that the SAA gene superfamily comprises a cluster of closely linked genes localized to 11p15.1. Pulsed field gel electrophoresis placed SAA1 within 350 kb of the previously linked SAA2 and SAA4 genes. Fluorescence in situ hybridization using a cosmid probe carrying the SAA2 and SAA4 genes refined the localization of the genes to 11p15.1. A highly polymorphic (CA)n dinucleotide repeat within the SAA3 pseudogene was typed in the CEPH reference families and found to map also in the 11p15.1 region, proximal to the parathyroid hormone gene (PTH; 168450) and distal to D11S455.
Watson et al. (1994) used fluorescence in situ hybridization analysis and PCR amplification of DNA from 17 somatic cell hybrids carrying all or part of chromosome 11 as their only human component to demonstrate that the entire SAA superfamily is located at 11p15. Furthermore, they demonstrated that SAA1, SAA2, and SAA4, i.e., all of the functional genes of the superfamily, map within the region 11p15.4-p15.1.
Sellar et al. (1994) demonstrated that the human SAA gene family encompasses approximately 150 kb. SAA1 and SAA2 are 15 to 20 kb apart and are arranged in divergent transcriptional orientations. SAA4 is 9 kb downstream of SAA2 and in the same orientation. SAA3 is 110 kb downstream of SAA4; its relative orientation could not be determined. Using interphase fluorescence in situ hybridization, Sellar et al. (1994) found the following gene order: cen--LDHC--LDHA--SAA1--SAA2--SAA4--SAA3--TPH--D11SA8--KCNC1--MYOD1--pter.
Kluve-Beckerman and Song (1995) showed that the SAA1 and SAA2 genes are arranged in a head-to-head transcriptional orientation about 18 kb apart. SAA4, the third functional serum amyloid locus, is 11 kb from SAA2 and in the same orientation. A fifth SAA clone isolated from this library was noncontiguous with the other 4 and contained the SAA3 pseudogene.
Svatikova et al. (2003) found that plasma SAA levels were more than 2-fold greater in patients with moderate to severe obstructive sleep apnea (107650) compared with subjects with mild obstructive sleep apnea or healthy controls regardless of gender. The authors concluded that elevated SAA may contribute to any increased risk for cardiovascular and neuronal dysfunction in patients with obstructive sleep apnea.
Kluve-Beckerman et al. (1986) demonstrated RFLPs of the SAA gene.
Stevens et al. (1993) described a HindIII RFLP in the SAA1 gene and found distinctive allele frequencies in Negroids and San (formerly 'Bushmen') in South Africa.
Cazeneuve et al. (2000) found that patients with familial Mediterranean fever (249100) and homozygosity for the SAA1-alpha polymorphism had a 7-fold increased risk for renal amyloidosis, compared with other SAA1 genotypes. Heterozygotes had no such increased risk, and no increased risk was found with any SAA2 polymorphism. The amino acid composition of the alpha, beta, and gamma isoforms of SAA1 are, respectively, V52-A57, A52-V57, and A52-A57.
Lundmark et al. (2002) noted that AA amyloidosis occurs in patients with rheumatoid arthritis and other chronic inflammatory diseases, and also can be induced experimentally in mice in which SAA concentrations are markedly increased by injection of silver nitrate, casein, or lipopolysaccharide. Within 2 or 3 weeks after the inflammatory stimulus, animals develop systemic AA deposits, as found in patients with AA amyloidosis. This lag phase is dramatically shortened when mice are given, concomitantly, an intravenous injection of protein extracted from AA amyloid-laden mouse spleen or liver. The amyloidogenic accelerating activity of such preparations was termed 'amyloid enhancing factor' (AEF). Lundmark et al. (2002) reported that the active principle of AEF is unequivocally the AA fiber itself. Further, they demonstrated that this material is extremely potent, being active in doses less than 1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. They concluded that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.
By isoelectric focusing, Kluve-Beckerman et al. (1991) identified an allelic variant of SAA in a family of Turkish origin: a G-to-A transition in codon 72, which resulted in substitution of aspartic acid for glycine. Beach et al. (1992) found the same gly72-to-asp allelic variant.
Baba et al. (1995) described an allelic variant of the SAA1 gene that they proposed may represent an important risk factor for the development of reactive amyloid systemic amyloidosis, also called AA-amyloidosis. The variant, termed SAA1-gamma, was found in pooled acute-phase serum, using mass spectrometry. SAA1-gamma has alanines at amino acid positions 52 and 57, whereas the previously known SAA1 variants, SAA1-alpha and SAA1-beta, have a valine at position 52 or 57, respectively, instead of an alanine. These SAA1s are the 3 major isoforms of human SAA1. Baba et al. (1995) found that SAA1-gamma differed from SAA1-alpha at only 1 base; codon 52 was GCC (ala) in SAA1-gamma and GTC (val) in SAA1-alpha. They found a difference in the distribution of SAA1 genotypes with an increased frequency of gamma/gamma homozygotes in the AA-amyloid group (0.60 vs 0.18).
Baba, S., Masago, S. A., Takahashi, T., Kasama, T., Sugimura, H., Tsugane, S., Tsutsui, Y., Shirasawa, H. A novel allelic variant of serum amyloid A, SAA1-gamma: genomic evidence, evolution, frequency, and implication as a risk factor for reactive systemic AA-amyloidosis. Hum. Molec. Genet. 4: 1083-1087, 1995. [PubMed: 7655463] [Full Text: https://doi.org/10.1093/hmg/4.6.1083]
Bausserman, L. L., Herbert, P. N., McAdam, K. P. W. J. Heterogeneity of human serum amyloid A proteins. J. Exp. Med. 152: 641-656, 1980. [PubMed: 6774048] [Full Text: https://doi.org/10.1084/jem.152.3.641]
Bausserman, L. L., Saritelli, A. L., Herbert, P. N., McAdam, K. P. W. J., Shulman, R. S. NH2-terminal analysis of four of the polymorphic forms of human serum amyloid A proteins. Biochim. Biophys. Acta 704: 556-559, 1982. [PubMed: 6810934] [Full Text: https://doi.org/10.1016/0167-4838(82)90082-6]
Beach, C. M., De Beer, M. C., Sipe, J. D., Loose, L. D., De Beer, F. C. Human serum amyloid A protein: complete amino acid sequence of a new variant. Biochem. J. 282: 615-620, 1992. [PubMed: 1546977] [Full Text: https://doi.org/10.1042/bj2820615]
Betts, J. C., Edbrooke, M. R., Thakker, R. V., Woo, P. The human acute-phase serum amyloid A gene family: structure, evolution and expression in hepatoma cells. Scand. J. Immun. 34: 471-482, 1991. [PubMed: 1656519] [Full Text: https://doi.org/10.1111/j.1365-3083.1991.tb01570.x]
Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Genevieve, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.-C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S. Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am. J. Hum. Genet. 67: 1136-1143, 2000. [PubMed: 11017802] [Full Text: https://doi.org/10.1016/S0002-9297(07)62944-9]
Kluve-Beckerman, B., Drumm, M. L., Benson, M. D. Nonexpression of the human serum amyloid A three (SAA3) gene. DNA Cell Biol. 10: 651-661, 1991. [PubMed: 1755958] [Full Text: https://doi.org/10.1089/dna.1991.10.651]
Kluve-Beckerman, B., Long, G. L., Benson, M. D. DNA sequence evidence for polymorphic forms of human serum amyloid A (SAA). Biochem. Genet. 24: 795-803, 1986. [PubMed: 3800865] [Full Text: https://doi.org/10.1007/BF00554519]
Kluve-Beckerman, B., Malle, E., Vitt, H., Pfeiffer, C., Benson, M., Steinmetz, A. Characterization of an isoelectric focusing variant of SAA1 (asp-72) in a family of Turkish origin. Biochem. Biophys. Res. Commun. 181: 1097-1102, 1991. [PubMed: 1764061] [Full Text: https://doi.org/10.1016/0006-291x(91)92051-k]
Kluve-Beckerman, B., Naylor, S. L., Marshall, A., Gardner, J. C., Shows, T. B., Benson, M. D. Localization of human SAA gene(s) to chromosome 11 and detection of DNA polymorphisms. Biochem. Biophys. Res. Commun. 137: 1196-1204, 1986. [PubMed: 3015139] [Full Text: https://doi.org/10.1016/0006-291x(86)90352-9]
Kluve-Beckerman, B., Song, M. Genes encoding human serum amyloid A proteins SAA1 and SAA2 are located 18 kb apart in opposite transcriptional orientations. Gene 159: 289-290, 1995. [PubMed: 7622070] [Full Text: https://doi.org/10.1016/0378-1119(95)00027-4]
Lundmark, K., Westermark, G. T., Nystrom, S., Murphy, C. L., Solomon, A., Westermark, P. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Nat. Acad. Sci. 99: 6979-6984, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 100: 3543 only, 2003. [PubMed: 12011456] [Full Text: https://doi.org/10.1073/pnas.092205999]
Sack, G. H., Jr., Talbot, C. C., Jr., Seuanez, H., O'Brien, S. J. Molecular analysis of the human serum amyloid A (SAA) gene family. Scand. J. Immun. 29: 113-119, 1989. [PubMed: 2564214] [Full Text: https://doi.org/10.1111/j.1365-3083.1989.tb01105.x]
Sack, G. H., Jr. Molecular cloning of human genes for serum amyloid A. Gene 21: 19-24, 1983. [PubMed: 6301947] [Full Text: https://doi.org/10.1016/0378-1119(83)90143-9]
Sellar, G. C., Jordan, S. A., Bickmore, W. A., Fantes, J. A., van Heyningen, V., Whitehead, A. S. The human serum amyloid A protein (SAA) superfamily gene cluster: mapping to chromosome 11p15.1 by physical and genetic linkage analysis. Genomics 19: 221-227, 1994. [PubMed: 8188252] [Full Text: https://doi.org/10.1006/geno.1994.1051]
Sellar, G. C., Oghene, K., Boyle, S., Bickmore, W. A., Whitehead, A. S. Organization of the region encompassing the human serum amyloid A (SAA) gene family on chromosome 11p15.1. Genomics 23: 492-495, 1994. [PubMed: 7835903] [Full Text: https://doi.org/10.1006/geno.1994.1530]
Sipe, J. D., Colten, H. R., Goldberger, G., Edge, M. D., Tack, B. F., Cohen, A. S., Whitehead, A. S. Human serum amyloid A (SAA): biosynthesis and postsynthetic processing of preSAA and structural variants defined by complementary DNA. Biochemistry 24: 2931-2936, 1985. [PubMed: 3839415] [Full Text: https://doi.org/10.1021/bi00333a018]
Stevens, G., Ramsay, M., Kluve-Beckerman, B., Jenkins, T. A new Negroid-specific HindIII polymorphism in the serum amyloid A1 (SAA1) gene increases the usefulness of the SAA locus in linkage studies. Genomics 15: 242-243, 1993. [PubMed: 8094371] [Full Text: https://doi.org/10.1006/geno.1993.1050]
Strachan, A. F., Brandt, W. F., Woo, P., van der Westhuyzen, D. R., Coetzee, G. A., de Beer, M. C., Shephard, E. G., de Beer, F. C. Human serum amyloid A protein: the assignment of the six major isoforms to three published gene sequences and evidence for two genetic loci. J. Biol. Chem. 264: 18368-18373, 1989. [PubMed: 2808379]
Svatikova, A., Wolk, R., Shamsuzzaman, A. S., Kara, T., Olson, E. J., Somers, V. K. Serum amyloid A in obstructive sleep apnea. Circulation 108: 1451-1454, 2003. [PubMed: 12952844] [Full Text: https://doi.org/10.1161/01.CIR.0000089091.09527.B8]
Taylor, B. A., Rowe, L. Genes for serum amyloid A proteins map to chromosome 7 in the mouse. Molec. Gen. Genet. 195: 491-499, 1984. [PubMed: 6088946] [Full Text: https://doi.org/10.1007/BF00341452]
Watson, G., See, C. G., Woo, P. Use of somatic cell hybrids and fluorescence in situ hybridization to localize the functional serum amyloid A (SAA) genes to chromosome 11p15.4-p15.1 and the entire SAA superfamily to chromosome 11p15. Genomics 23: 694-696, 1994. [PubMed: 7851899] [Full Text: https://doi.org/10.1006/geno.1994.1559]