Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK1
Cytogenetic location: 5q15 Genomic coordinates (GRCh38): 5:96,390,333-96,433,248 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q15 | {Obesity, susceptibility to, BMIQ12} | 612362 | 3 | |
| Endocrinopathy due to proprotein convertase 1/3 deficiency | 600955 | Autosomal recessive | 3 |
Proprotein convertase-1 (EC 3.4.21.93) is a neuroendocrine convertase that belongs to a family of subtilisin-like serine endoproteases that process large precursor proteins into mature bioactive products. Other members of this family include furin (136950), which acts within the constitutive secretory pathway, and PC2 (PCSK2; 162151), which, like PC1, is involved in tissue-specific processing of prohormones and neuropeptide precursors within the regulated neuroendocrine secretory pathway (Jansen et al., 1995).
Using a mouse PC1 probe to screen a human pituitary cDNA library, Seidah et al. (1992) isolated a PC1 cDNA predicted to encode a 753-amino acid protein with a cAMP-dependent protein kinase serine phosphorylation site, a tyrosine kinase phosphorylation site, and an arg-gly-asp (RGD) sequence. The protein shares 92.6% sequence identity with the mouse homolog, with the highest homology (98%) in the catalytic segment of the molecule (residues 84-399). Northern blot analysis of human tissues detected a major 6.2-kb mRNA transcript, with smaller transcripts in some tissues. Expression was highest in pituitary and brain, and lower in pancreas and heart.
Jansen et al. (1995) identified and characterized the PC1 promoter region. They found that it directs high levels of neuroendocrine-specific expression both for basal expression and cAMP-mediated hormonal regulation.
Ohagi et al. (1996) showed that the human PC3 gene contains 14 exons. The exon/intron organization of the PC2 and PC3 genes are conserved, consistent with a common evolutionary origin.
By in situ hybridization, Seidah et al. (1991) mapped the NEC1 gene to human chromosome 5q15-q21 and mouse chromosome 13. Copeland et al. (1992) refined the regional localization on mouse chromosome 13.
PC1 and PC2 differentially cleave proopiomelanocortin (POMC; 176830), and they act together to process proinsulin and proglucagon in pancreatic islets (Jansen et al., 1995).
Ohagi et al. (1996) noted that PC1 initiates the sequential processing of proinsulin to insulin (176730) by cleaving the proinsulin molecule on the C-terminal side of the dibasic peptide, arg31-arg32, joining the B-chain and C-peptide. PC2 is responsible for cleavage of the C-peptide/A-chain junction of the proinsulin molecule. Expression of insulin and PC1, but not PC2, is coordinately regulated by glucose, consistent with the important role of PC1 in regulating proinsulin processing.
By directed mutagenesis, Ueda et al. (2003) studied the role of various amino acids in PC3 in determining the structure and therefore the function of the protein.
By observing the phenotypic features in patients with PC1 mutations, Jackson et al. (2003) concluded that human intestinal absorptive function is dependent on PC1 activity.
Proprotein Convertase 1/3 Deficiency
In a patient with extreme childhood obesity, abnormal glucose homeostasis, hypogonadotropic hypogonadism, hypocortisolism, elevated plasma proinsulin and POMC concentrations, but very low insulin levels, suggestive of defective prohormone processing (see 600955) (O'Rahilly et al., 1995), Jackson et al. (1997) identified compound heterozygosity for mutations in the PC1 gene (162150.0001-162150.0002). Jackson et al. (1997) noted the phenotypic similarities in this patient to the fat/fat mouse, a model of obesity, which is caused by mutation in carboxypeptidase E (CPE; 114855), an enzyme active in the processing and sorting of prohormones (see Naggert et al., 1995; Cool et al., 1997). The authors noted that PC1 acts proximally to CPE in prohormone processing. Mutations in the CPE gene had not been demonstrated in human obesity.
In an infant with proprotein convertase-1 deficiency (600955), Jackson et al. (2003) identified compound heterozygosity for mutations in the PC1 gene (162150.0003-162150.0004).
In a 6-year-old boy, born of consanguineous parents of Libyan origin, with persistent diarrhea and severe hyperphagia and obesity, Farooqi et al. (2007) identified homozygosity for a mutation in the PCSK1 gene (S307L; 162150.0006).
Wilschanski et al. (2014) identified a homozygous missense mutation in the PCSK1 gene (N309K; 162150.0007) in 4 Arab sibs, born to consanguineous parents, with proprotein convertase-1 deficiency. The mutation was not present in the Exome Variant Server database. When PCSK1 with the N209K mutation was expressed in HEK293 and Neuro2A cells, the secreted enzyme showed no catalytic activity and was not processed to the 66-kD form, indicating that there was no self-cleavage. Radiolabeling experiments in Neuro2A cells showed that PCSK1 with the N209K mutation was able to undergo prodomain removal and generate an 87-kD form.
In a patient, born to consanguineous Turkish parents, with proprotein convertase-1 deficiency, Pepin et al. (2019) identified a homozygous nonsense mutation in the PCSK1 gene (R199X; 162150.0008). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents.
Martin et al. (2013) identified homozygous mutations in the PCSK1 gene in 13 patients with proprotein convertase-1 deficiency from 11 families, 10 of which were consanguineous. One patient (patient 2) had 2 homozygous mutations (G209R and P258T). The mutations included 5 missense, 4 nonsense, 1 deletion (162150.0011), and 2 splice site mutations (IVS10+1G-T, 162150.0009; IVS10+1G-A, 162150.0010). Expression of PCKS1 with each mutation in HEK293 cells resulted in most with a lack of secreted enzyme activity, including all of the nonsense mutations and the deletion. PCKS1 with the F548S was secreted but was inactive, and PCKS1 with the P258T and N432K had reduced enzyme activity. None of the mutations were present in the dbSNP or 1000 Genomes Project databases.
Polygenic Obesity Risk
Benzinou et al. (2008) genotyped tag SNPs in a total of 13,659 individuals of European ancestry from 8 independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D (162150.0005), and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity. The N221D mutation induced a 10.4% significant reduction of activity (P = 0.03) when compared to the wildtype PC1/3. The functional data suggested a modest deleterious role of the N221D mutation, but no significant effect of the Q665E-S690T amino acid substitutions was identified. Benzinou et al. (2008) showed that the rs6234-rs6235 pair was independently associated with obesity, and found 5 noncoding SNPs that were in high linkage disequilibrium with rs6234-rs6235.
Zhu et al. (2002) reported that disruption of the PC1 gene in mice results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary POMC, proinsulin, and proglucagon. Pc1-null mice had normal blood corticosterone levels and no impairment of glucose tolerance. In contrast to humans with PC1 mutations, the Pc1-null mice were not obese.
In Japanese patients with noninsulin-dependent diabetes mellitus (NIDDM; 125853), which is associated with increased secretion of proinsulin and proinsulin-like molecules, Ohagi et al. (1996) could find no mutation in the PC1 gene associated with NIDDM.
In a woman with proprotein convertase-1 deficiency (600955), Jackson et al. (1997) identified compound heterozygosity for 2 mutations of the PCSK1 gene: a gly483-to-arg (G483R) substitution of one allele, and an A-C transversion at +4 of the intron 5 donor splice site (162150.0002). The latter mutation resulted in skipping of exon 5, loss of 26 residues, a frameshift, and creation of a premature stop codon within the catalytic domain of the enzyme. Three of the woman's 4 clinically unaffected children had the G483R missense mutation, while the fourth child had the splice site mutation. The proband's fasting serum leptin (164160) concentration was appropriate for her body mass index.
For discussion of the splice site mutation (IVS5+4A-C) in the PCSK1 gene that was found in compound heterozygous state in a patient with proprotein convertase-1 deficiency (600955) by Jackson et al. (1997), see 162150.0001.
In an infant with proprotein convertase-1 deficiency (600955), Jackson et al. (2003) identified compound heterozygosity for 2 mutations in the PC1 gene: a 937G-T nonsense mutation, glu250-to-ter (E250X), and a 3-bp deletion (162150.0004), resulting in the deletion of a conservative alanine at residue 213. The nonsense mutation was predicted to truncate the PC1 protein within the catalytic domain.
For discussion of the 3-bp deletion in the PCSK1 gene, resulting in deletion of ala213, that was found in compound heterozygous state in an infant with proprotein convertase-1 deficiency (600955) by Jackson et al. (2003), see 162150.0003.
Benzinou et al. (2008) genotyped tag SNPs in a total of 13,659 individuals of European ancestry from 8 independent case-control or family-based cohorts. The nonsynonymous variant rs6232, encoding an asn-to-asp substitution at codon 221 (N221D) of the PCSK1 gene, was consistently associated with obesity (BMIQ12, 612362) in adults and children, with a P value of 7.27 x 10(-8). Functional analysis indicated that the N221D mutation induced a 10.4% significant reduction of activity (P = 0.03) of the PC1/3 enzyme when compared to wildtype PC1/3.
In a 6-year-old boy with proprotein convertase-1 deficiency (600955), born of consanguineous parents of Libyan origin, Farooqi et al. (2007) identified homozygosity for a ser307-to-leu (S307L) substitution in the catalytic domain of PCSK1. The boy presented with persistent diarrhea, severe hyperphagia, and obesity. Both parents were heterozygous for the mutation and were not obese; the mutation was not found in 100 control alleles of Arab origin. Although intracellular trafficking of the mutant enzyme appeared normal and S307L retained some autocatalytic activity, it was completely inactive on other substrates.
In 4 Arab sibs, born to consanguineous parents, with proprotein convertase-1 deficiency (600955), Wilschanski et al. (2014) identified a homozygous c.927C-G transition in the PCSK1 gene, resulting in an asn309-to-lys (N209K) substitution. The mutation, which was identified by a combination of SNP genotyping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation was not present in the Exome Variant Server database. Expression of PCSK1 with the N209K mutation in HEK293 cells showed no catalytic activity.
In a patient, born to consanguineous Turkish parents, with proprotein convertase-1 deficiency (600955), Pepin et al. (2019) identified a homozygous c.595C-T transition (c.595C-T, NM_000439.4) in exon 5 of the PCSK1 gene, resulting in an arg199-to-ter (R199X) substitution in the catalytic domain. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. The mutation resulted in loss of the C-terminal and P domains and a large portion of the catalytic domain, and likely caused loss of function of the protein. The mutation was present in the gnomAD database with an allele frequency of 0.003%.
In a Turkish patient (family 3), born to consanguineous parents, with proprotein convertase-1 deficiency (600955), Martin et al. (2013) identified homozygosity for a c.1095+1G-T transition in the intron 8 splice donor site of the PCSK1 gene. The mutation was identified by sequencing of the PCSK1 gene and was present in the carrier state in the parents. The mutation was not present in the dbSNP or 1000 Genomes databases. (In the article by Martin et al. (2013), the intron was stated to be intron 8 in figure 1 and table 1, but as intron 10 in figure 2.)
In a Turkish patient (family 7), born to consanguineous parents, with proprotein convertase-1 deficiency (600955), Martin et al. (2013) identified homozygosity for a c.1095+1G-A transversion in the intron 8 splice donor site of the PCSK1 gene. The mutation was identified by sequencing of the PCSK1 gene and was present in the carrier state in the parents. The mutation was not present in the dbSNP or 1000 Genomes databases. (In the article by Martin et al. (2013), the intron was stated to be intron 8 in figure 1 and table 1, but as intron 10 in figure 2.)
In an Arab patient (family 8), born to consanguineous parents, with proprotein convertase-1 deficiency (600955), Martin et al. (2013) identified homozygosity for a 4-bp deletion (c.1349_1352delTGGA) predicted to result in a frameshift and premature termination (Val450fsTer1). The mutation was identified by sequencing of the PCSK1 gene and was present in the carrier state in the parents. The mutation was not present in the dbSNP or 1000 Genomes databases. Expression of PCKS1 with the 1349_1352delTGGA mutation in HEK293 cells resulted in lack of enzyme activity.
Benzinou, M., Creemers, J. W. M., Choquet, H., Lobbens, S., Dina, C., Durand, E., Guerardel, A., Boutin, P., Jouret, B., Heude, B., Balkau, B., Tichet, J., and 20 others. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nature Genet. 40: 943-948, 2008. [PubMed: 18604207] [Full Text: https://doi.org/10.1038/ng.177]
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Ohagi, S., Sakaguchi, H., Sanke, T., Tatsuta, H., Hanabusa, T., Nanjo, K. Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Diabetes 45: 897-901, 1996. [PubMed: 8666140] [Full Text: https://doi.org/10.2337/diab.45.7.897]
Pepin, L., Colin, E., Tessarech, M., Rouleau, S., Bouhours-Nouet, N., Bonneau, D., Coutant, R. A new case of PCSK1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review. J. Clin. Endocr. Metab. 104: 985-993, 2019. [PubMed: 30383237] [Full Text: https://doi.org/10.1210/jc.2018-01854]
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Seidah, N. G., Mattei, M. G., Gaspar, L., Benjannet, S., Mbikay, M., Chretien, M. Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Genomics 11: 103-107, 1991. [PubMed: 1765368] [Full Text: https://doi.org/10.1016/0888-7543(91)90106-o]
Ueda, K., Lipkind, G. M., Zhou, A., Zhu, X., Kuznetsov, A., Philipson, L., Gardner, P., Zhang, C., Steiner, D. F. Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1). Proc. Nat. Acad. Sci. 100: 5622-5627, 2003. [PubMed: 12721373] [Full Text: https://doi.org/10.1073/pnas.0631617100]
Wilschanski, M., Abbasi, M., Blanco, E., Lindberg, I., Yourshaw, M., Zangen, D., Berger, I., Shteyer, E., Pappo, O., Bar-Oz, B., Martin, M. G., Elpeleg, O. A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity. PLoS One 9: e108878, 2014. [PubMed: 25272002] [Full Text: https://doi.org/10.1371/journal.pone.0108878]
Yourshaw, M., Solorzano-Vargas, R. S., Pickett, L. A., Lindberg, I., Wang, J., Cortina, G., Pawlikowska-Haddal, A., Baron, H., Venick, R. S., Nelson, S. F., Martin, M. G. Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. J. Pediat. Gastroent. Nutr. 57: 759-767, 2013. [PubMed: 24280991] [Full Text: https://doi.org/10.1097/MPG.0b013e3182a8ae6c]
Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., Laurent, V., Lindberg, I., Ugleholdt, R., Holst, J. J., Steiner, D. F. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Nat. Acad. Sci. 99: 10293-10298, 2002. [PubMed: 12145326] [Full Text: https://doi.org/10.1073/pnas.162352599]