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HGNC Approved Gene Symbol: PRH1
Cytogenetic location: 12p13.2 Genomic coordinates (GRCh38): 12:10,880,965-11,171,611 (from NCBI)
The acidic and basic proline-rich proteins constitute about two-thirds of the parotid salivary proteins and have important functions at tooth surfaces. Parotid acidic protein (Pa) was studied by Friedman et al. (1975) and Friedman and Merritt (1975). They suggested that Pa, Pr (168790) and Db may be determined by separate but closely situated genes. Azen and Denniston (1974) presented data indicating linkage between Pr and Db. Yu et al. (1978) concluded that the most likely order is Pr-Pa-Db. The maximum lod score for Pr:Pa was 2.7 at theta 0.03; for Pr:Db, 3.8 at theta 0.12; for Pa:Db, 1.6 at theta 0.19. Yu et al. (1978) favored gene order Pa-Pr-Db, but the relative odds over second order Pr-Pa-Db were small.
According to the hypothesis of Maeda (1985), the 3 acidic PRPs, Db, Pa, and PIF, are coded for by alleles at a single locus rather than by 3 discrete loci. The hypothesis is based on DNA studies which suggest that 6 loci control the synthesis of the PRPs. Genes at 2 of these loci, PRH1 and PRH2 (so named because they contain repeated cleavage sites for the restriction enzyme HaeIII), code for the acidic PRPs. Genes at the remaining 4 loci (PRB1, PRB2, PRB3, and PRB4) contain regions that strongly hybridize to a probe with repeated BstNI sites; they probably code for the basic and glycosylated PRPs. This hypothesis of 6 loci forming 2 gene subfamilies contrasts with that based on protein polymorphisms in families that suggest 13 loci with 11 common null alleles. (This situation is reminiscent of the competing hypotheses to explain the genetics of the ABO blood groups. Population data were important to the resolution of the problem. Von Dungern and Hirschfeld (1910), who showed that the ABO blood groups are indeed inherited, proposed a 2-locus theory, i.e., suggested that there are separate loci for A/non-A and B/non-B. Bernstein (1924) showed that a 1-locus, 3-allele hypothesis best fitted the family and especially the population data (see Stern, 1973).) Maeda et al. (1985) showed that the discrepancy between the studies of PRP polymorphism and the DNA studies is explained by differential RNA processing and posttranslational modification by proteolysis, whereby 6 genes can code a larger number of proteins. Sequencing and restriction mapping indicate that the PRP cluster is in a segment of DNA about 500 kb long (Maeda, 1985). The 2 genes PRH1 and PRH2 (168790) have been completely sequenced (Kim and Maeda, 1986). The sequence information confirms the allelic relationship of Db, Pa, and PIF. Db protein product is longer by 21 amino acids.
O'Connell et al. (1987) placed the PRB cluster of genes distal to KRAS2 (190070). Furthermore, they concluded that the 4 PRB genes are oriented as follows: cen--PRB2--PRB1--(PRB3,4)--12pter. The PRP genes are on mouse chromosome 8. Unlike humans, rats and mice do not normally show expression of these genes, which can, however, be induced by the beta-adrenergic agonist isoproterenol and by dietary sorghums with high tannin levels. As reviewed by Azen et al. (1986), the PRP genes and a cluster of taste genes are closely linked in the mouse. O'Hanlon et al. (1988) demonstrated that the PTC tasting gene (171200) is not linked to the salivary proline-rich protein genes in man.
Azen and Denniston (1981) found that PIF shows a high order of heterozygosity in whites, blacks, and Chinese. Studies in 41 families supported the genetic control of PIF by a single autosomal locus. A lod score of 3.56 at theta of 0.00 was found for PIF versus G1 (168840). (PIF has also been used as the symbol for prolactin release-inhibiting factor, 152760.) Azen et al. (1987) cloned and sequenced the entire exon and intron structures of Db and Pa genetic determinants at the PRH1 locus. The amino acid sequences derived therefrom and that previously determined for the PIF protein completely explained the electrophoretic phenotypes of the 3 acidic proline-rich proteins. The cysteine substitution near arginine 106 in the Pa protein sterically interferes with proteolytic cutting at arg106 and accounts for the single-banded phenotype. In contrast, the Db and PIF proteins are proteolytically cut at arg106 and show a double-banded phenotype. The Db protein has an extra 21-amino acid repeat that accounts for its larger size compared with the other 2 proteins. These DNA/protein correlations, as well as the highly similar genomic/DNA sequences that differ by less than 1%, caused Azen et al. (1987) to conclude that Pa, Db, and PIF are alleles at the PRH1 locus. The Db and Pa alleles appear to have diverged more recently from a common precursor than did the PIF allele from its precursor.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). Azen and Maeda (1988) reviewed the molecular genetics of the salivary proteins, giving gene frequencies for the polymorphisms.
Azen, E. A. Genetic protein polymorphism in human saliva: an interpretive review. Biochem. Genet. 16: 79-99, 1978. [PubMed: 348195] [Full Text: https://doi.org/10.1007/BF00484386]
Azen, E. A., Denniston, C. Genetic polymorphism of PIF (parotid isoelectric focusing variant) proteins with linkage to the PPP (parotid proline-rich protein) gene complex. Biochem. Genet. 19: 475-485, 1981. [PubMed: 7295285] [Full Text: https://doi.org/10.1007/BF00484620]
Azen, E. A., Denniston, C. L. Genetic polymorphism of human salivary proline-rich proteins: further genetic analysis. Biochem. Genet. 12: 109-120, 1974. [PubMed: 4424642] [Full Text: https://doi.org/10.1007/BF00487820]
Azen, E. A., Kim, H.-S., Goodman, P., Flynn, S., Maeda, N. Alleles at the PRH1 locus coding for the human salivary-acidic proline-rich proteins Pa, Db, and PIF. Am. J. Hum. Genet. 41: 1035-1047, 1987. [PubMed: 3687941]
Azen, E. A., Lush, I. E., Taylor, B. A. Close linkage of mouse genes for salivary proline-rich proteins (PRPs) and taste. Trends Genet. 2: 199-200, 1986.
Azen, E. A., Maeda, N. Molecular genetics of human salivary proteins and their polymorphisms. Adv. Hum. Genet. 17: 141-199, 1988. [PubMed: 3055850] [Full Text: https://doi.org/10.1007/978-1-4613-0987-1_5]
Bernstein, F. Ergebnisse einer biostatischen zusammenfassenden Betrachtung ueber die erblichen Blutstrukturen des Menschen. Klin. Wschr. 3: 1495-1497, 1924.
Bernstein, F. Zusammenfassende Betrachtungen ueber die erblichen Blutstrukten des Menschen. Z. indukt. Abstamm. u. VererbLehre 37: 237-270, 1925. Note: Translation: Blood Transfusion Division, U.S. Army Medical Research Laboratory, Fort Knox, Kentucky 40121.
Friedman, R. D., Merritt, A. D. Partial purification and characterization of a polymorphic protein (Pa) in human parotid saliva. Am. J. Hum. Genet. 27: 304-314, 1975. [PubMed: 803013]
Friedman, R. D., Merritt, A. D., Rivas, M. L. Genetic studies of human acidic salivary protein (Pa). Am. J. Hum. Genet. 27: 292-303, 1975. [PubMed: 803012]
Ikemoto, S., Minaguchi, K., Hinohara, H. Genetic polymorphisms of human parotid salivary proteins (Pa, Pb, Pr, Db and Pm) and salivary amylase isozyme in Japanese population. Hum. Hered. 27: 328-331, 1977. [PubMed: 903160] [Full Text: https://doi.org/10.1159/000152886]
Kim, H.-S., Maeda, N. Structures of two HaeIII-type genes in the human salivary proline-rich protein multigene family. J. Biol. Chem. 261: 6712-6718, 1986. [PubMed: 3009472]
Maeda, N. Inheritance of the human salivary proline-rich proteins: a reinterpretation in terms of six loci forming two subfamilies. Biochem. Genet. 23: 455-464, 1985. [PubMed: 3840016] [Full Text: https://doi.org/10.1007/BF00499086]
Maeda, N., Kim, H.-S., Azen, E. A., Smithies, O. Differential RNA splicing and post-translational cleavages in the human salivary proline-rich protein gene system. J. Biol. Chem. 260: 11123-11130, 1985. [PubMed: 2993301]
O'Connell, P., Lathrop, G. M., Law, M., Leppert, M., Nakamura, Y., Hoff, M., Kumlin, E., Thomas, W., Elsner, T., Ballard, L., Goodman, P., Azen, E., Sadler, J. E., Cai, G. Y., Lalouel, J.-M., White, R. A primary genetic linkage map for human chromosome 12. Genomics 1: 93-102, 1987. [PubMed: 3478299] [Full Text: https://doi.org/10.1016/0888-7543(87)90110-8]
O'Hanlon, K., Weissbecker, K., Cortessis, V., Spence, M. A., Azen, E. A. Genes for salivary proline-rich proteins and taste for phenylthiourea are not closely linked in humans. Cytogenet. Cell Genet. 49: 315-317, 1988. [PubMed: 2907874] [Full Text: https://doi.org/10.1159/000132687]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Stern, C. Principles of Human Genetics. (3rd ed.) San Francisco: W. H. Freeman (pub.) 1973. Pp. 256-262.
von Dungern, E., Hirschfeld, L. Ueber Vererbung gruppenspezifischer Strukturen des Blutes. II. Z. Immunforsch. 6: 284-292, 1910. Note: Translation: G. P. Pohlmann: Transfusion 2: 70-74, 1962.
Yu, P. L., Karn, R. C., Merritt, A. D. Multipoint mapping of the human parotid salivary proteins: Pr, Pa, Db. (Abstract) Am. J. Hum. Genet. 30: 129A only, 1978.
Yu, P. L., Schwartz, R. C., Merritt, A. D., Azen, E. A., Rivas, M. L., Karn, R. C., Craft, M. A. Linkage relationships of the proline-rich salivary proteins (Pr, Pa, Db). Cytogenet. Cell Genet. 22: 655-658, 1978. [PubMed: 752561] [Full Text: https://doi.org/10.1159/000131046]