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HGNC Approved Gene Symbol: PRB1
Cytogenetic location: 12p13.2 Genomic coordinates (GRCh38): 12:11,351,821-11,355,591 (from NCBI)
Azen and Maeda (1988) reviewed the proline-rich proteins (PRP) of saliva, which are encoded by 6 closely linked loci on chromosome 12p. The proteins fall into acidic and basic groups. The 2 genes that encode acidic proteins are PRH1 (168730) and PRH2 (168790), and these genes contain repeated sequences that have a cleavage site for the restriction enzyme HaeIII. The PRH1 locus codes for the Pa, Db, and PIF proteins. The PRH2 locus codes for the Pr protein. The 4 genes that encode basic proline-rich proteins are PRB1, PRB2 (168810), PRB3 (168840), and PRB4 (180990), and these genes contain repeated sequences that have a cleavage site for the restriction enzyme BstNI. The PRB1 locus encodes the PmF, PmS, Pe, and Con2 proteins. The PRB2 locus encodes the Ps and Con1 proteins. The PRB3 locus encodes the G1 protein. The PRB4 locus encodes the Po protein.
In parotid saliva of a Japanese population, Ikemoto et al. (1977) found 2 phenotypes by electrophoresis in acid-urea starch gels. The protein showing polymorphism was located in the zone between Pa and the protein labeled Pb (for protein basic) and thus was termed the parotid middle band protein (Pm). Inheritance was autosomal dominant. The frequency of the Pm(+) allele was about 0.38 in Japanese.
Azen and Denniston (1980) showed linkage of Pm and Ps to the Pa-Pr-Db-G1 cluster. On the basis of weak linkage disequilibrium, Ps may be closer to G1 and Db than to Pa or Pr. Azen and Denniston (1980) provided evidence for close linkage to 5 other parotid salivary protein loci.
Yu et al. (1980) presented evidence for linkage between Pa and Pr and between Pr and Db. No significant sex heterogeneity in recombination was found. Significant sex heterogeneity of recombination between Pa and Db was found, but the lod score for males did not reach the level usually accepted as proof of linkage. Population studies suggested linkage disequilibrium among the three loci. Kauffman et al. (1982) found a single amino acid difference between PmF and PmS proteins when a portion of their primary structure was compared. From somatic cell genetic studies using a human genomic probe, Goodman et al. (1984) concluded that the cluster of genes encoding proline-rich proteins is located on chromosome 12 and possibly on 12p since it could be excluded from the 12cen-q24 segment. The human SPC (salivary protein complex) may extend over a map length of about 15 cM; in comparison, the major histocompatibility complex has a map length of about 1.8 cM. Against the proposed genetic length of 15 cM is the conclusion of Maeda (1986) that the 6 genes of the complex are contained in a 500-kb segment of DNA. (One cM is approximately 1,000 kb.) (Pm consists of 2 proteins, a fast and a slow electrophoretic form, called PmF and PmS, respectively.)
Azen and Yu (1984) defined another polymorphism in the proteins of parotid saliva. Called Pe, it was typed after protein staining in alkaline polyacrylamide slab gels. The Pe+ allele had a frequency of about 0.76 in both whites and blacks. From randomly collected samples, the Pe+ protein was most strongly associated with the Con1 and Ps proteins, less strongly associated with Pr and Pa proteins, and not significantly associated with PmF, PmS, PIF, Db, Con2, or G1 proteins. If it is assumed that the strength of these associations is related in part to map distance, then these data roughly fit the preferred linear order of PRP genes as previously determined by family linkage studies: Ps-Pa-Pr-Pm-G1-Db. Pe was linked to Pa with maximum lod score of 2.69 at theta = 0.0.
In a full review of salivary proteins, Azen and Maeda (1988) stated that the 6 genes encoding proline-rich proteins are in a 700-kb interval in the following order: PRB2--(60 kb)--PRB1--(70 kb)--PRB4--(190 kb)--PRH2--(160 kb)--PRB3--(190 kb)--PRH1.
Kim et al. (1993) presented the nucleotide sequences of 4 members of the 6-member human salivary proline-rich protein family: PRB1 and PRB2, which encode basic PRPs, and PRB3 and PRB4, which encode glycosylated PRPs. Each gene is approximately 4 kb long and contains 4 exons, the third of which is entirely composed of 63-bp tandem repeats and encodes the proline-rich portion of the protein products. Exon 3 contains different numbers of tandem repeats in the different PRB genes. Variation in the numbers of these repeats is also responsible for length variations in different alleles of the PRB genes.
Comparison of the nucleotide sequences of the 6 PRP genes by Kim et al. (1993) suggested that they probably evolved from a single ancestral gene by 4 sequential gene duplications, leading to 6 genes that fall into 3 subsets, each consisting of 2 genes. During this evolutionary process, multiple rearrangements in gene conversion events occurred mainly in the region between the 3-prime end of IVS2 and the 3-prime end of exon 3.
Azen, E., Lyons, K. M., McGonigal, T., Barrett, N. L., Clements, L. S., Maeda, N., Vanin, E. F., Carlson, D. M., Smithies, O. Clones from the human gene complex coding for salivary proline-rich proteins. Proc. Nat. Acad. Sci. 81: 5561-5565, 1984. [PubMed: 6089212] [Full Text: https://doi.org/10.1073/pnas.81.17.5561]
Azen, E. A., Denniston, C. Polymorphism of Ps (parotid size variant) and detection of a protein (PmS) related to the Pm (parotid middle band) system with genetic linkage of Ps and Pm to G1, Db, and Pr genetic determinants. Biochem. Genet. 18: 483-501, 1980. [PubMed: 7437007] [Full Text: https://doi.org/10.1007/BF00484396]
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]
Azen, E. A., Yu, P. L. Genetic polymorphism of Pe and Po salivary proteins with probable linkage of their genes to the SPC (salivary protein complex). Biochem. Genet. 22: 1065-1081, 1984. [PubMed: 6529438] [Full Text: https://doi.org/10.1007/BF00499632]
Azen, E. A., Yu, P. L. Two new saliva markers, Pe and Po, probably linked in the SPC. (Abstract) Am. J. Hum. Genet. 36: 5S only, 1984.
Goodman, P. A., Lalley, P. A., Azen, E. A. Salivary proline-rich protein genes on chromosome 12 of man. (Abstract) Am. J. Hum. Genet. 36: 202S only, 1984.
Ikemoto, S., Minaguchi, K., Suzuki, K., Tomita, K. New genetic markers in human parotid saliva (Pm). Science 197: 378-379, 1977. [PubMed: 877561] [Full Text: https://doi.org/10.1126/science.877561]
Karn, R. C., Friedman, R. D., Merritt, A. D. Human salivary proline-rich (Pr) proteins: a posttranslational derivation of the phenotypes. Biochem. Genet. 17: 1061-1077, 1979. [PubMed: 540000] [Full Text: https://doi.org/10.1007/BF00504345]
Kauffman, D., Wong, R., Bennick, A., Keller, P. Basic proline-rich proteins from human parotid saliva: complete covalent structure of protein 1B-9 and partial structure of protein 1B-6, members of a polymorphic pair. Biochemistry 21: 6558-6562, 1982. [PubMed: 6924859] [Full Text: https://doi.org/10.1021/bi00268a036]
Kim, H. S., Lyons, K. M., Saitoh, E., Azen, E. A., Smithies, O., Maeda, N. The structure and evolution of the human salivary proline-rich protein gene family. Mammalian Genome 4: 3-14, 1993. [PubMed: 8422499] [Full Text: https://doi.org/10.1007/BF00364656]
Maeda, N. Personal Communication. Madison, Wis. 9/12/1986.
Minaguchi, K., Ikemoto, S., Suzuki, K. Isolation and partial characterization of a polymorphic protein (Pm) in human parotid saliva. Biochem. Genet. 19: 617-621, 1981. [PubMed: 7295289] [Full Text: https://doi.org/10.1007/BF00484630]
Yu, P.-L., Karn, R. C., Merritt, A. D., Azen, E. A., Conneally, P. M. Linkage relationships and multipoint mapping of the human parotid salivary proteins (Pr, Pa, Db). Am. J. Hum. Genet. 32: 555-563, 1980. [PubMed: 7395868]
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]