Alternative titles; symbols
HGNC Approved Gene Symbol: CTRC
Cytogenetic location: 1p36.21 Genomic coordinates (GRCh38): 1:15,438,443-15,449,242 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.21 | {Pancreatitis, chronic, susceptibility to} | 167800 | Autosomal dominant | 3 |
Tomomura et al. (1992) purified a serum calcium-decreasing factor, which they called caldecrin, from porcine pancreas. Tomomura et al. (1995) cloned a rat cDNA containing the gene encoding caldecrin. The primary structure of the rat cDNA was found to be, with the exception of that of the central region, almost identical to that of elastase IV (Kang et al., 1992). The predicted protein was presumed to be synthesized as a 268-amino acid preproenzyme with a 16-residue signal peptide and a 13-residue activation peptide.
Tomomura et al. (1996) isolated 2 homologous cDNA clones encoding caldecrin from human pancreas; the structures of the 2 were identical except for 1 base change and the corresponding amino acid residue substitution. These human caldecrin isoforms, like the rat preproenzyme, are composed of a signal peptide of 16 amino acids, a propeptide of 13 amino acids, and a mature form of 239 amino acids. Both recombinant caldecrins, produced in a baculovirus expression system, showed the same chymotrypsin-type protease activity (118888) and hypocalcemic activity. The hypocalcemic activity of both caldecrin isoforms remained intact even after treatment with phenylmethylsulfonyl fluoride (PMSF) to abolish their protease activity.
The CTRC gene comprises 8 exons and spans 8.2 kb (Rosendahl et al., 2008).
The digestive protease trypsin (276000) has a fundamental pathogenetic role in chronic pancreatitis (167800). Rosendahl et al. (2008) analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, R254W (601405.0001) and K247_R254del (601405.0002), were significantly overrepresented in the pancreatitis group. A replication study identified these 2 variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease. CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis (608189) but only 1 of 84 (1.2%) healthy controls. Functional analysis of these CTRC variants showed impaired activity and/or reduced secretion. The results indicated that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.
Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis and 350 controls and identified 2 common variants and 19 rare variants. The combined frequency of the rare variants in patients with sporadic chronic pancreatitis was significantly higher than that of controls (12% versus 1.1%; OR, 11.8; p less than 10(-6)).
In a study of 901 individuals with idiopathic or hereditary chronic pancreatitis (167800) and 2,804 control subjects of German origin, Rosendahl et al. (2008) found that a 760C-T transition in exon 7 of the CTRC gene, resulting in an arg254-to-trp amino acid substitution (R254W), was significantly overrepresented among affected individuals (19/901; 2.1%, P = 0.0004) compared to controls (18/2804; 0.6%). Investigation of an independent cohort of 348 German individuals with alcohol-related chronic pancreatitis and 432 controls confirmed this finding (2.3% in affected individuals vs 0.5% in controls). Enrichment of the R254W variant in 71 Indian subjects with tropical pancreatitis (608189) did not reach statistical significance.
Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis and identified the R254W mutation in 5 sporadic patients and 1 of 350 controls.
Rosendahl et al. (2008) found that a 24-bp in-frame deletion in exon 7 of the CTRC gene (738_761del24, lys247_arg254del) was significantly overrepresented among 901 individuals of German origin with idiopathic or hereditary chronic pancreatitis (167800) (1.2%) compared to 2,804 German controls (0.1%, P = 0.00003). Allele frequency was 0.6% among 348 German individuals with alcohol-related chronic pancreatitis and 0.2% among 432 controls. This variant was not found among 71 Indian subjects with tropical pancreatitis (608189) and 84 controls of Indian origin.
Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis and identified the 24-bp deletion at nucleotide 738 in 2 sporadic patients and 1 of 350 controls.
Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis (167800) and 350 controls, and in 1 patient they identified a 164G-A transition in exon 3, resulting in a trp55-to-ter (W55X) substitution in the CTRC gene.
Kang, J., Wiegand, U., Muller-Hill, B. Identification of cDNAs encoding two novel rat pancreatic serine proteases. Gene 110: 181-187, 1992. [PubMed: 1537555] [Full Text: https://doi.org/10.1016/0378-1119(92)90646-7]
Masson, E., Chen, J.-M., Scotet, V., Le Marechal, C., Ferec, C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum. Genet. 123: 83-91, 2008. [PubMed: 18172691] [Full Text: https://doi.org/10.1007/s00439-007-0459-3]
Rosendahl, J., Witt, H., Szmola, R., Bhatia, E., Ozsvari, B., Landt, O., Schulz, H.-U., Gress, T. M., Ptufzer, R., Lohr, M., Kovacs, P., Bluher, M., and 22 others. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nature Genet. 40: 78-82, 2008. [PubMed: 18059268] [Full Text: https://doi.org/10.1038/ng.2007.44]
Tomomura, A., Akiyama, M., Itoh, H., Yoshino, I., Tomomura, M., Nishii, Y., Noikura, T., Saheki, T. Molecular cloning and expression of human caldecrin. FEBS Lett. 386: 26-28, 1996. [PubMed: 8635596] [Full Text: https://doi.org/10.1016/0014-5793(96)00377-8]
Tomomura, A., Fukushige, T., Noda, T., Noikura, T., Saheki, T. Serum calcium-decreasing factor (caldecrin) from porcine pancreas has proteolytic activity which has no clear connection with the calcium decrease. FEBS Lett. 301: 277-281, 1992. [PubMed: 1577166] [Full Text: https://doi.org/10.1016/0014-5793(92)80256-g]
Tomomura, A., Tomomura, M., Fukushige, T., Akiyama, M., Kubota, N., Kumaki, K., Nishii, Y., Noikura, T., Saheki, T. Molecular cloning and expression of serum calcium-decreasing factor (caldecrin). J. Biol. Chem. 270: 30315-30321, 1995. [PubMed: 8530454] [Full Text: https://doi.org/10.1074/jbc.270.51.30315]