Alternative titles; symbols
HGNC Approved Gene Symbol: ORM1
Cytogenetic location: 9q32 Genomic coordinates (GRCh38): 9:114,323,098-114,326,479 (from NCBI)
Alpha-1-acid glycoprotein, or orosomucoid, is a relatively abundant plasma protein synthesized in the liver. It has a molecular weith of 40,000 Da and is a single polypeptide chain of about 180 amino acids. AGP is considered an acute phase reactant; its plasma levels increase several fold during acute infections (summary by Dente et al., 1985).
Board et al. (1986) isolated a cDNA clone for ORM and compared the derived amino acid sequence with preexisting data.
Dente et al. (1988) studied the regulation of AGP-A by transfecting cell lines and preparing transgenic mice with constructs including the entire AGP gene. The AGP constructs were expressed with comparable efficiency in hepatoma and HeLa cells; however, these same constructs were expressed in transgenic mice in a tissue-specific manner. The mRNA was found solely in the liver. These authors found that a 6.6-kb segment consisting of the entire coding region plus 1.2 kb of 5-prime-flanking and 2 kb of 3-prime-flanking DNA contained sufficient information for tissue-specific, regulated expression of the gene.
Tomei et al. (1989) generated families of transgenic mice carrying various orosomucoid genes and studied the ORM variants secreted into the serum of the mice.
Board et al. (1986) presented the complete nucleotide sequence encoding orosomucoid.
Dente et al. (1987) cloned the genomic DNA segment encoding orosomucoid and showed that it contains 3 adjacent coding regions which they designated acid glycoprotein (AGP)-A, AGP-B, and AGP-B-prime. The regions were identical in exon-intron organization but had slightly different coding potentials. These results accounted for the heterogeneity observed by protein sequencing. Southern blot analysis indicated that the cloned cluster contains all the orosomucoid coding sequences present in the human genome. Most of the alpha-AGP mRNA in human liver is transcribed from AGP-A, whose promoter and cap site have been determined, while the level of AGP-B and B-prime mRNA in human liver is very low.
The tandemly arranged ORM1 and ORM2 (138610) genes (also designated AGP1 and AGP2, respectively) span about 11.5 kb. Each gene contains 6 exons and encodes a 183-amino acid polypeptide (Yuasa et al., 1997).
The structural gene for orosomucoid (ORM1) was assigned to the end of the long arm of chromosome 9 by demonstration of linkage to ABO and AK1 (Eiberg et al., 1982). The male lod score for ORM versus ABO was 5.06 at theta 0.27; for ABO versus AK, 6.27 at theta 0.13; for ORM versus AK, 1.63 at theta 0.17. Thus, the order was judged to be ORM-AK-ABO.
Cox and Francke (1985) used hybrids of human fetal liver and rat hepatoma cells to study the location of the genes for serum proteins. In this way they gave direct assignment of the orosomucoid gene to chromosome 9 and the alpha-2-HS-glycoprotein gene to chromosome 3, these having been previously assigned by linkage to 'anchor' loci. Rocchi et al. (1986) confirmed the assignment of ORM to chromosome 9 by Southern blot analysis of DNA from somatic cell hybrids using a cDNA probe.
On the basis of studies in members of 3 Newfoundland kindreds with the same specific chromosome 9 aberration, an inverted paracentric insertion, inv ins(9)(q22.1q34.3q34.1), Allderdice et al. (1986) concluded that ORM is located in 9q34.3-qter.
Gene cloning studies by Dente et al. (1985) suggested that there are at least 2 genes coding for alpha-1-AGP. Webb et al. (1988) likewise concluded that there are at least 2 genes for alpha-1-acid glycoprotein (alpha-1-AGP) that are in close proximity; by in situ hybridization, ORM1 and ORM2 appeared to be located in 9q31-q34.1. On the basis of a normal ORM1 level in a child with a deletion 9q32-qter secondary to a balanced maternal translocation, Zuffardi et al. (1989) concluded that ORM1 may be located in the region 9q31-q32.
Variants of orosomucoid have been demonstrated in the blood of normal Caucasians and Japanese (Schmid et al., 1965). Johnson et al. (1969) presented twin and family data supporting the view that 3 phenotypes, SS, FF and FS, are determined by 2 codominant alleles.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Using a new method for ORM phenotyping, Eap et al. (1988) discovered a rare variant tentatively assigned to the ORM2 locus (138610) and a common variant tentatively assigned to the ORM1 locus. Umetsu et al. (1988) reported on polymorphism of ORM1 and ORM2 in a population in the Philippines. ORM2 was nonpolymorphic, i.e., monomorphic, in that population when studied by that method. ORM2 is polymorphic in Japan (see 138610). Luckenbach et al. (1991) reported family studies of ORM1 subtyping.
Yuasa et al. (1993) reported on a total of 57 different alleles at the ORM1 and ORM2 loci, including 17 newly identified ones. Twenty-seven were assigned to the ORM1 locus and 30 to the ORM2 locus. They proposed a revised system of nomenclature.
Yuasa et al. (1997) noted that in plasma, ORM proteins are presented as a mixture of ORM1 and ORM2 proteins in a molar ratio of 3:1, respectively. Classic genetic polymorphism occurs in the more abundant ORM1, which is controlled by the ORM1 locus. ORM1*F, the 'fast' allele, is divided into 2 subtype alleles, ORM1*F1 and ORM1*F2. ORM1*F1 and ORM1*S are observed worldwide and ORM1*F2 is also common in European populations. The ORM2 locus is monomorphic in most populations. Yuasa et al. (1997) stated that about 30 rare variant alleles had been distinguished electrophoretically at each of the loci.
Yuasa et al. (1997) investigated the molecular basis of ORM1 polymorphism. For the detection of mutations, PCR-amplified products of the 6 exons of the gene were screened by SSCP analysis. Sequencing of the PCR products showed that the 3 common ORM1 alleles result from A-to-G transitions at codons for amino acid position 20 in exon 1 and 156 in exon 5.
Polymorphism of ORM proteins was first discovered after starch gel electrophoresis of desialyzed samples by Tokita and Schmid (1963), who proposed that the variation is controlled by 2 alleles, ORM*F and ORM*S, for fast and slow, at a single locus. The ORM1 locus is highly polymorphic, and ORM1*F is divided into 2 subtype alleles, ORM1*F1 and ORM1*F2. ORM1*F1 and ORM1*S are observed worldwide and ORM1*F2 is also common in European populations. Yuasa et al. (1997) demonstrated that these 3 common ORM1 alleles result from A-to-G transitions at the codons for amino acid positions 20 in exon 1 and 156 in exon 5 of the AGP1 gene: ORM1*F1 is characterized by CAG (gln) and GTG (val); ORM1*F2, by CAG (gln) and ATG (met); and ORM1*S, by CGG (arg) and GTG (val). Yuasa et al. (1997) discussed the phylogeny of these 3 ORM1 alleles.
See 138600.0001 and Yuasa et al. (1997).
See 138600.0001 and Yuasa et al. (1997).
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