Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PRSS2
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:142,770,970-142,774,560 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q34 | {Pancreatitis, chronic, protection against} | 167800 | Autosomal dominant | 3 |
Rowen et al. (1996) sequenced completely the human beta T-cell receptor locus (TCRB; see 186930), comprising a complex family of genes. The locus contains 2 types of coding elements: TCR elements (65 variable gene segments and 2 clusters of diversity, joining, and constant segments) and 8 trypsinogen genes. The coding elements constitute 4.6% of the DNA of the region. The total sequence was 685 kb in length. The 8 trypsinogen genes are embedded in the locus, raising a question as to whether their association arises from functional or regulatory constraints, or is inadvertent. The intercalation of the trypsinogen genes in the TCRB locus is conserved in mouse and chicken, suggesting shared functional or regulatory constraints, as has been postulated for genes in the major histocompatibility complex (such as class I, II, and III) that share similar long-term organizational relationships. Alignment of pancreatic trypsinogen cDNAs with the germline sequences showed that these trypsinogen genes contain 5 exons that span approximately 6 kb. Further analyses revealed 2 trypsinogen pseudogenes and 1 relic trypsinogen gene at the 5-prime end of the sequence, all in inverted transcriptional orientation. They denoted the 8 trypsinogen genes T1 through T8 from 5-prime to 3-prime. Rowen et al. (1996) found that only 2 of 3 pancreatically expressed trypsinogen cDNAs correspond to trypsinogen genes in the TCRB locus; T4 was denoted trypsinogen 1 (276000) and T8 was denoted trypsinogen 2. The third pancreatic cDNA, identified independently as trypsinogen 3 and 4, is distinct from the third apparently functional trypsinogen gene (T6) in the TCRB locus but related to the other pancreatic trypsinogens. Rowen et al. (1996) stated that the T6 gene is deleted in a common insertion-deletion polymorphism; if it is functional, its function is apparently not essential. Some of the trypsinogen genes are expressed in nonpancreatic tissues where their function is unknown.
Rowen et al. (1996) mapped the gene corresponding to the third pancreatic trypsinogen cDNA by fluorescence in situ hybridization. They used a cosmid clone containing 3 trypsinogen genes. Strong hybridization to chromosome 7 and weaker hybridization to chromosome 9 were observed. They isolated and partially sequenced 4 cosmid clones from the chromosome 9 region. They found that the region represents a duplication and translocation of a DNA segment from the 3-prime end of the TCRB locus that includes at least 7 V(beta) elements and a functional trypsinogen gene denoted T9. The assignment of the PRSS1 gene to 7q35 is established by the demonstration of its sequence within the sequence of the 'locus' (186930) for the T-cell receptor beta-chain (Rowen et al., 1996). It is further supported by the linkage between microsatellite markers in the 7q35 region and hereditary pancreatitis (167800) and the demonstration of mutations in the PRSS1 gene in hereditary pancreatitis.
Teich et al. (2004) demonstrated that the E79K mutation in PRSS1 (276000.0006) activated anionic trypsinogen 2-fold better than wildtype cationic trypsin did, whereas the common pancreatitis-associated mutants R122H (276000.0001) and N29I (276000.0002) had no such effect. The observations not only suggested a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlighted the importance of interactions between the 2 major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.
Because increased proteolytic activity owing to mutated PRSS1 (276000) enhances the risk for chronic pancreatitis (167800), Witt et al. (2006) suspected that mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. In an analysis of PRSS2 in individuals with chronic pancreatitis and controls, they found, to their surprise, that a variant of codon 191 (G191R; 601546.0001) was overrepresented in control subjects.
Witt et al. (2006) described a variant of the PRSS2 gene, gly191 to arg (G191R), that was protective against the development of chronic pancreatitis (167800). The substitution arose from a G-to-A transition in exon 4. The G191R mutation was present in 220 of 6,459 (3.4%) controls but in only 32 of 2,466 (1.3%) affected individuals (odds ratio 0.37). Upon activation by enterokinase (PRSS7; 606635) or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. Witt et al. (2006) concluded that the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.
Rowen, L., Koop, B. F., Hood, L. The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science 272: 1755-1762, 1996. [PubMed: 8650574] [Full Text: https://doi.org/10.1126/science.272.5269.1755]
Teich, N., Le Marechal, C., Kukor, Z., Caca, K., Witzigmann, H., Chen, J.-M., Toth, M., Mossner, J., Keim, V., Ferec, C., Sahin-Toth, M. Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). Hum. Mutat. 23: 22-31, 2004. [PubMed: 14695529] [Full Text: https://doi.org/10.1002/humu.10285]
Witt, H., Sahin-Toth, M., Landt, O., Chen, J.-M., Kahne, T., Drenth, J. P. H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.-U., and 53 others. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nature Genet. 38: 668-673, 2006. [PubMed: 16699518] [Full Text: https://doi.org/10.1038/ng1797]