Alternative titles; symbols
HGNC Approved Gene Symbol: CPA1
Cytogenetic location: 7q32.2 Genomic coordinates (GRCh38) : 7:130,380,494-130,388,108 (from NCBI)
Carboxypeptidase A (EC 3.4.2.1) is a pancreatic exopeptidase. The A1 and A2 (600688) forms are monomeric proteins with different biochemical properties. See also pancreatic carboxypeptidase B (114852).
Catasus et al. (1992) cloned the A1 form of pancreatic procarboxypeptidase using antibodies to screen an expression library of human pancreatic cDNA. The cDNA contains a reading frame encoding 419 amino acids and is very similar to the A1 forms from rat and bovine pancreatic glands.
Carboxypeptidase A1 is one of the genes whose expression in the pancreas was demonstrated by Velculescu et al. (1995) with a novel method for serial analysis of gene expression (SAGE). The method allowed the quantitative and simultaneous analysis of a large number of transcripts. To demonstrate the strategy, short diagnostic sequence tags (SSTs) were isolated from pancreas, concatenated, and cloned. Manual sequencing of 1,000 tags revealed a gene expression pattern characteristic of pancreas. New pancreatic transcripts corresponding to novel tags were also identified. SAGE is based on 2 principles: first, that a short nucleotide sequence tag (9 to 10 bp) contained sufficient information to uniquely identify a transcript; and second, that concatenation of SSTs allows the efficient analysis of transcripts in a serial manner by the sequencing of multiple tags within a single clone. Using SAGE, Velculescu et al. (1995) found that procarboxypeptidase A1 was the gene represented by the tag found most frequently in the pancreatic transcripts (7.6%). The authors suggested that SAGE should allow a direct readout of expression in any given cell type or tissue. They envisioned a major application to be the comparison of gene expression patterns in various developmental and disease states. Any laboratory with the capability to perform PCR and manual sequencing could perform SAGE for this purpose. Adaptation of this technique to an automated sequencer would allow the analysis of over 1,000 transcripts in a single 3-hour run.
Honey et al. (1984, 1986) found that an 8.6-kb human DNA fragment (detected by means of a rat cDNA probe for CPA) cosegregated with chromosome 7. The assignment was narrowed by demonstration of absence of the human DNA fragment in cells with a deletion of 7q22-qter. By studying mouse-hamster hybrid cells, Honey et al. (1986) assigned the CPA gene to mouse chromosome 6. Trypsin (276000) is also on human 7q22-qter and on mouse 6. Stewart et al. (1990) concluded from multipoint linkage analysis with established chromosome 7 markers that the most likely location of carboxypeptidase is 7q31-qter. It lies distal to cystic fibrosis at a distance of approximately 12 cM.
Gross (2019) mapped the CPA1 gene to chromosome 7q32.2 based on an alignment of the CPA1 sequence (GenBank BC005279) with the genomic sequence (GRCh38).
Witt et al. (2013) analyzed CPA1 in subjects with nonalcoholic chronic pancreatitis (see 167800) (cases) and controls in a German discovery set and 3 replication sets. Functionally impaired variants were present in 29 (3.1%) of 944 German cases and 5 (0.1%) of 3,938 controls (OR = 24.9, p = 1.5 x 10(-16)). The association was strongest in subjects aged less than 10 years (9.7%; OR = 84.0, p = 4.1 x 10(-24)). In the replication sets, defective CPA1 variants were present in 8 (1.3%) of 600 cases and 9 (0.4%) of 2,432 controls from Europe (p = 0.01); 5 (2.2%) of 230 cases and 0 of 264 controls from India (p = 0.02); and 5 (2.0%) of 247 cases and 0 of 341 controls from Japan (p = 0.013.). Witt et al. (2013) proposed that the mechanism by which CPA1 variants confer increased pancreatitis risk might involve misfolding-induced endoplasmic reticulum (ER) stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.
Hegyi and Sahin-Toth (2019) found that mouse Cpa1 with an asn256-to-lys (N256K) mutation, corresponding to the most frequently occurring human CPA1 variant, was retained intracellularly and induced ER stress when expressed in HEK293T cells, modeling the effects of the human variant. Mice with homozygous knockin of the N256K mutation in Cpa1 showed no phenotypic alterations, bred normally, and gained weight with similar kinetics compared with wildtype. Pancreas of knockin mice had normal morphology but weighed significantly less than wildtype. Knockin mice developed spontaneous and progressive chronic pancreatitis and exhibited signs of ER stress in pancreas. In addition, knockin mice had high plasma amylase and intrapancreatic trypsin activity during disease course.
Catasus, L., Villegas, V., Pascual, R., Aviles, F. X., Wicker-Planquart, C., Puigserver, A. cDNA cloning and sequence analysis of human pancreatic procarboxypeptidase A1. Biochem. J. 287: 299-303, 1992. [PubMed: 1417781] [Full Text: https://doi.org/10.1042/bj2870299]
Gross, M. B. Personal Communication. Baltimore, Md. 9/18/2019.
Hegyi, E, Sahin-Toth, M. Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. Gut 68: 301-312, 2019. [PubMed: 30045879] [Full Text: https://doi.org/10.1136/gutjnl-2018-315994]
Honey, N. K., Sakaguchi, A. Y., Lalley, P. A., Quinto, C., Rutter, W. J., Naylor, S. L. Assignment of the gene for carboxypeptidase A to human chromosome 7q22-qter and to mouse chromosome 6. Hum. Genet. 72: 27-31, 1986. [PubMed: 3455919] [Full Text: https://doi.org/10.1007/BF00278813]
Honey, N. K., Sakaguchi, A. Y., Quinto, C., MacDonald, R. J., Rutter, W. J., Naylor, S. L. Assignment of the human genes for elastase to chromosome 12, and for trypsin and carboxypeptidase A to chromosome 7 (Abstract) Cytogenet. Cell Genet. 37: 492, 1984.
Stewart, E. A., Craik, C. S., Hake, L., Bowcock, A. M. Human carboxypeptidase A identifies a BglII RFLP and maps to 7q31-qter. Am. J. Hum. Genet. 46: 795-800, 1990. [PubMed: 1969228]
Velculescu, V. E., Zhang, L., Vogelstein, B., Kinzler, K. W. Serial analysis of gene expression. Science 270: 484-487, 1995. [PubMed: 7570003] [Full Text: https://doi.org/10.1126/science.270.5235.484]
Witt, H., Beer, S., Rosendahl, J., Chen, J.-M., Candak, G. R., Masamune, A., Bence, M., Szmola, R., Oracz, G., Macek, M., Jr., Bhatia, E., Steigenberger, S., and 54 others. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nature Genet. 45: 1216-1220, 2013. [PubMed: 23955596] [Full Text: https://doi.org/10.1038/ng.2730]