HGNC Approved Gene Symbol: HPR
Cytogenetic location: 16q22.2 Genomic coordinates (GRCh38): 16:72,063,226-72,077,246 (from NCBI)
The HPR gene is the product of a segmental duplication of the HP gene (140100) on chromosome 16. Like HP, HPR binds hemoglobin (Hb) with high affinity. Together with apolipoprotein L1 (APOL1; 603743), HPR-Hb forms a protein complex called trypanosome lytic factor-1 (TLF1), which plays an important role in protection against Trypanosoma brucei, the pathogen that causes trypanosomiasis, or sleeping sickness (summary by Hardwick et al., 2014).
Bensi et al. (1985) and Maeda (1985) isolated the human HPR gene. Its predicted amino acid sequence differs by about 8% from that of the electrophoretically fast-migrating HP variant (HP1F; 140100.0001). The differences appeared to be located on the surface of the protein molecule, and the regions and specific residues considered to be important for binding hemoglobin are identical in the HP and HPR proteins.
Smithies and Powers (1986) found evidence of gene conversion (see 142200) between the closely linked HP and HPR loci.
Maeda and Kim (1990) demonstrated that the 2 genes in the human haptoglobin cluster, HP and HPR, contain 2 retrovirus-like elements. One (RTVL-Ia) is in the first intron of the HPR gene, and the second (RTVL-Ic) is at the 3-prime-end of the gene cluster. In the chimpanzee 3-gene cluster (HP-HPR-HPP), there is an additional retrovirus-like element (RTVL-Ib) in the intergenic region between the chimpanzee HPR and HPP loci. RTVL-Ia and RTVL-Ib are essentially full size and have the general structure 5-prime-LTR--gag--pol-env--3-prime-LTR, while RTVL-Ic lacks about one-third of its 5-prime portion. Although none of the elements had retained long open reading frames, Maeda and Kim (1990) detected stretches with amino acids identical to various parts of proteins of the Moloney murine leukemia virus (Mo-MuLV). They concluded that the RTVL-I elements were derived from a virus similar in structure to Mo-MuLV. The DNA sequences surrounding the insertion points of the 3 RTVL-I elements were dissimilar, implying that they integrated into the haptoglobin gene cluster independently at some time after the initial formation of the triplicated gene cluster in primates. Comparison of the nucleotide sequences of the 3 elements suggested that foreign DNA introduced into the genome can accumulate mutations more rapidly than the genomic sequences surrounding them. At least 5 other families of retrovirus-like sequences have been found in the human genome; for a review, see Cohen and Larsson (1988). In RTVL-I, the tRNA used for the primer binding site is ile-tRNA. (RTVL-I = retrovirus-like sequence--isoleucine.)
The HPR gene maps to chromosome 16q22.1 (Bensi et al., 1985; Maeda, 1985).
Maeda et al. (1986) found that the HPR gene(s) lie on the downstream side of the HP gene (140100).
Using immobilized hemoglobin for affinity chromatography, Nielsen et al. (2006) showed that HPR could bind hemoglobin as efficiently as HP, and SDS-PAGE showed that HPR migrated as a 45-kD monomer and a 90-kD dimer. In contrast to HP, HPR did not promote high-affinity binding to CD163 (605545). Western blot analysis of 18 persons with normal HP levels and 13 patients with low HP levels resulting from sickle cell anemia and extensive intravascular hemolysis indicated that the plasma concentration of HPR was unaffected by hemolysis, suggesting that depletion of HP but not HPR in these patients may be a consequence of the difference in CD163 binding between HP-hemoglobin and HPR-hemoglobin complexes. Binding of hemoglobin to circulating native HPR incorporated in the high density lipoprotein (HDL) fraction was indicated by hemoglobin-affinity precipitation of plasma HPR together with APOL1. Nielsen et al. (2006) suggested that hemoglobin reported to be present in TLF represents HPR-bound hemoglobin, which may contribute to the biologic activity of circulating TLF.
The protozoan parasite Trypanosoma brucei is lysed by APOL1, a component of HDL particles that are also characterized by the presence of HPR. Vanhollebeke et al. (2008) reported that this process is mediated by a parasite glycoprotein receptor, which binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. In mice, this receptor was required for optimal parasite growth and the resistance of parasites to the oxidative burst by host macrophages. In humans, the trypanosome receptor also recognized the complex between hemoglobin and HPR, which explains its ability to capture trypanolytic HDLs. Vanhollebeke et al. (2008) concluded that, in humans, the presence of HPR has diverted the function of the trypanosome haptoglobin-hemoglobin receptor to elicit innate host immunity against the parasite.
During pregnancy, HPR circulates in plasma; furthermore, Kuhajda et al. (1989) demonstrated that HPR or HPR-like epitopes are expressed in human breast carcinoma. This led Kuhajda et al. (1989) to examine the possibility that anti-HPR immunoreactivity of biopsy specimens from women with primary breast carcinoma might be related to the clinical behavior of the tumor. They examined the association between the expression of HPR and the recurrence of cancer in a retrospective study of 70 patients with early breast cancer treated by mastectomy from 1977-1985 at the Johns Hopkins Hospital. Expression of HPR epitopes was associated with earlier recurrence, and multivariate analysis showed that HPR-epitope expression was an independent prognostic factor. The authors concluded that it is a clinically important predictor of recurrence, especially in combination with progesterone-receptor status.
McEvoy and Maeda (1988) analyzed the evolutionary history of the haptoglobin gene family by characterizing the haptoglobin genes in primates. Whereas the HPR gene in the human is 2.2 kb downstream of the HP gene, chimpanzees, gorillas, orangutans, and Old World monkeys have a third gene, which McEvoy and Maeda (1988) named HPP for haptoglobin primate, located 16 kb downstream of HPR. New World monkeys have only 1 haptoglobin gene. McEvoy and Maeda (1988) interpreted these observations as suggesting triplication of the haptoglobin locus after divergence of the New World monkeys, followed by deletion of 1 locus in humans. They stated that, although in vivo transfection experiments indicated that the HPR promoter is active and cell-specific, no hemoglobin-binding protein of the expected structure had been detected.
Maeda et al. (1986) showed that tandemly arranged HPR genes are linked to the HP2 allele (140100.0002).
Maeda et al. (1986) found polymorphisms for the number of tandemly arranged HPR genes in the haptoglobin gene cluster in blacks. Such was not found in 26 whites and 1 Asian; all had a single HPR gene. In 1 black subject, 6 tandemly arranged HPR genes were demonstrated in 1 chromosome 16 by pulsed field gel electrophoresis; his other chromosome 16 had 1 HPR gene.
African trypanosomes cause disease in humans and animals. Trypanosoma brucei brucei affects cattle but not humans because of its sensitivity to a subclass of human high density lipoproteins called trypanosome lytic factor (TLF). TLF contains 2 apolipoproteins that are sufficient to cause lysis of T. b. brucei in vitro. Smith et al. (1995) identified these proteins as the human haptoglobin-related protein (HPR) and paraoxonase-arylesterase (PON; 168820). They found that an antibody to haptoglobin inhibited TLF activity. TLF was shown to exhibit peroxidase activity and to be inhibited by catalase. These results suggested that TLF kills trypanosomes by oxidative damage initiated by its peroxidase activity. As noted earlier, Maeda et al. (1986) found polymorphism for the number of tandemly arranged HPR genes in the haptoglobin gene cluster in blacks, whereas only a single HPR gene was found in other races. The work of Smith et al. (1995) raised the possibility that the development of the polymorphism was related to parasite exposure.
Using fiber-FISH, the paralog ratio test, and array-CGH data, Hardwick et al. (2014) confirmed that the HPR gene is copy number variable, with duplication of HPR occurring at polymorphic frequencies in west and central Africa, up to an allele frequency of 15%. High levels of HPR duplication overlapped the geographic region where chronic human African trypanosomiasis is endemic. Although the HPR duplication was somewhat undertransmitted to children affected by trypanosomiasis from unaffected parents in the Democratic Republic of Congo, the undertransmission became statistically significant when assessed together with alleles of APOL1 in these children.
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Vanhollebeke, B., De Muylder, G., Nielsen, M. J., Pays, A., Tebabi, P., Dieu, M., Raes, M., Moestrup, S. K., Pays, E. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science 320: 677-681, 2008. [PubMed: 18451305] [Full Text: https://doi.org/10.1126/science.1156296]