Alternative titles; symbols
HGNC Approved Gene Symbol: CPE
Cytogenetic location: 4q32.3 Genomic coordinates (GRCh38): 4:165,379,008-165,498,547 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
4q32.3 | BDV syndrome | 619326 | Autosomal recessive | 3 |
Carboxypeptidase E (CPE; EC 3.4.17.10) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin (INS; 176730) (Chen et al., 2001).
Manser et al. (1990) characterized CPE cDNAs from human and rat brain cDNA libraries. The deduced 476-amino acid human protein contains an N-terminal signal peptide, followed by a 'pro' sequence, a polyarginine stretch, and 2 potential N-glycosylation sites. CPE shares highest similarity with CPN (CPN1; 603103). Western blot analysis detected CPE proteins at apparent molecular masses of 50 and 48 kD in human and rat brain lysates, respectively. In vitro translated CPE was sensitive to deglycosylation, indicating that it is a glycoprotein.
Using immunohistochemical analysis, Carrel et al. (2009) detected an even distribution of Cpe along the dendrites of cultured rat hippocampal neurons. Fractionation of adult rat cortex revealed that Cpe localized with syntaxin (see STX1A, 186590), a neuronal plasma membrane marker. Rat brain Cpe was released from membranes at high pH, suggesting that Cpe is a peripheral membrane protein.
Hall et al. (1993) assigned the CPE gene to chromosome 4 by Southern analysis of a panel of somatic cell hybrid DNAs. Naggert et al. (1995) stated that the mouse Cpe gene maps to chromosome 8.
Cool et al. (1997) noted that secretory proteins in general are released from cells via a nonregulated constitutive pathway; however, in neuroendocrine cells of the nervous and endocrine systems, there is also a regulated secretory pathway (RSP) from which hormones, neuropeptides, and the granins are secreted in a calcium-dependent manner. The larger inactive proforms of these peptide hormones and neuropeptides are packaged into the granules of the RSP and are processed to active peptides intragranularly, although early processing steps may occur at the trans-Golgi network. The specific sorting of RSP proteins away from those destined for the plasma membrane or other compartments, e.g., lysosomes, is an active and selective process requiring a sorting signal. A proposed mechanism for sorting secretory proteins into granules for release via the regulated secretory pathway involved binding the proteins to a sorting receptor at the trans-Golgi network, followed by binding and granule formation. Cool et al. (1997) identified such a sorting receptor as membrane-associated CPE in pituitary Golgi-enriched and secretory granule membranes. CPE specifically bound regulated secretory pathway proteins, including prohormones, but not constitutively secreted proteins. Cool et al. (1997) showed that in the Cpe(fat) mutant mouse lacking Cpe (see ANIMAL MODEL), the pituitary prohormone proopiomelanocortin (POMC; 176830) was missorted to the constitutive pathway and secreted in an unregulated manner. Thus, obliteration of Cpe, the sorting receptor, led to multiple endocrine disorders of these genetically defective mice, including hyperproinsulinemia (176730) and infertility.
Carrel et al. (2009) found that overexpression of the long isoform of human NOS1AP (605551), called NOS1AP-L, reduced the outgrowth of primary and secondary dendrites in cultured rat hippocampal neurons. Yeast 2-hybrid analysis of rat brain lysates showed that an internal domain of NOS1AP-L bound Cpe, and this interaction was confirmed by immunoprecipitation analysis and protein pull-down assays. Knockdown of Cpe in rat hippocampal neurons abrogated the effect of NOS1AP-L overexpression, although knockdown of Cpe alone had little effect on dendrite branching. Carrel et al. (2009) concluded that an interaction between NOS1AP and CPE maintains immature dendritic morphology.
BDV Syndrome
In a 21-year-old Sudanese woman, born to consanguineous parents, with BDV syndrome (BDVS; 619326), Alsters et al. (2015) identified homozygosity for a frameshift mutation in the CPE gene (114855.0001).
In 3 Turkish sibs, born to consanguineous parents, with BDVS, Durmaz et al. (2020) identified homozygosity for a nonsense mutation (Y135X; 114855.0002) in the CPE gene.
In 4 patients from 3 unrelated families of Syrian, Egyptian, and Pakistani descent with BDVS, Bosch et al. (2021) identified homozygous mutations in the CPE gene (114855.0003 and 114855.0004).
Associations Pending Confirmation
One of the features of type 2 diabetes mellitus (T2D; 125853) is an elevation in the proinsulin level and/or molar ratio of proinsulin to insulin, suggesting that mutations in proinsulin processing enzymes may contribute to the development of this form of diabetes. Chen et al. (2001) scanned the CPE gene for mutations in a collection of Ashkenazi type 2 diabetes families and identified 5 novel SNPs. One of these, a C-to-T transition at nucleotide 847, led to an arg283-to-trp (R283W) change. The arg283 residue is conserved among CPE orthologs and most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi pedigrees with type 2 diabetes, Chen et al. (2001) found 4 families segregating R283W. Within these 4 families, patients who inherited one copy of this variant had much earlier age of onset of type 2 diabetes. The R283W CPE protein was found to cleave peptide substrates with substantially lower efficiencies and was, furthermore, less stable at elevated temperature. In addition, the R283W CPE variant had a narrower pH optimum and was much less active at pH 6.0 to 6.5, indicating that the R283W CPE variant would be substantially less active than wildtype CPE in the trans-Golgi network and immature secretory vesicles where the enzyme functions in vivo. Chen et al. (2001) predicted that in the homozygous state this mutant could cause hyperproinsulinemia and diabetes.
Naggert et al. (1995) stated that mice homozygous for the 'fat' mutation develop obesity and hyperglycemia that can be suppressed by treatment with exogenous insulin. The 'fat' mutation maps to mouse chromosome 8, close to the Cpe gene, which encodes an enzyme that processes prohormone intermediates such as proinsulin. Naggert et al. (1995) demonstrated a defect in proinsulin processing associated with the virtual absence of Cpe activity in extracts of fat/fat pancreatic islets and pituitaries. A single ser202-to-pro mutation distinguished the mutant Cpe allele and abolished enzymatic activity in vitro. Thus, the 'fat' mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.
Plum et al. (2009) generated mice with POMC (176830)-neuron-specific ablation of Foxo1 (136533) and observed an increase in Cpe expression that resulted in selective increases of alpha-Msh and beta-endorphin, which are the products of CPE-dependent processing of POMC. This neuropeptide profile was associated with decreased food intake and normal energy expenditure in the POMC-Foxo1 -/- mice. CPE expression was downregulated by diet-induced obesity, and Foxo1 deletion offset that decrease, protecting against weight gain. Leptin (164160) curtailed food intake more markedly in POMC-Foxo1 -/- mice than in wildtype mice, consistent with increased sensitivity to leptin; unexpectedly, there was also a near doubling of leptin levels in the POMC-Foxo1 -/- mice. Moderate Cpe overexpression in the arcuate nucleus phenocopied features seen in the POMC-Foxo1 -/- mice. Plum et al. (2009) concluded that Foxo1 ablation in hypothalamic POMC neurons reduces food intake without concurrently decreasing energy expenditure or leptin levels, and that this effect is mediated by CPE; they stated that this was the first time that hypophagia and reduced body weight had been uncoupled from energy expenditure and leptin levels.
In a 21-year-old Sudanese woman from a consanguineous family who had BDV syndrome (BDVS; 619326), Alsters et al. (2015) identified homozygosity for a 23-bp deletion (c.76_98del, NM_001873) in exon 1 of the CPE gene, resulting in a frameshift and a premature termination codon (Glu26ArgfsTer68). The authors noted that there was an exact 7-nucleotide repeat (GGGCGCC) at both breakpoints, suggesting a microhomology-mediated deletion mechanism. The mutation, which segregated with disease in the family, was not found in the 1000 Genomes Project or NHLBI Exome Sequencing Project databases, but was present in heterozygous state in 2 Caucasians in the ExAC database. DNA was unavailable from the proband's older brother, who died of unknown causes at age 21 years and also had childhood-onset severe obesity, impaired intellectual development, and hypogenitalism. RT-PCR in blood samples from the proband showed no CPE expression, whereas her heterozygous sister had an intermediate level compared with controls.
In 3 Turkish sibs, born to consanguineous parents, with BDV syndrome (BDVS; 619326), Durmaz et al. (2020) identified homozygosity for a c.405C-A transversion (c.405C-A, NM_001873.4) in the CPE gene, resulting in a tyr135-to-ter (Y135X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the ExAC or gnomAD databases or in an in-house database of 100 controls. Functional studies were not performed.
In 3 patients, including Syrian sibs (patients C-1 and C-2) and an unrelated Egyptian patient (patient D-1), all born to consanguineous parents, with BDV syndrome (BDVS; 619326), Bosch et al. (2021) identified homozygosity for a c.361C-T transition (c.361C-T, NM_001873.3) in exon 2 of the CPE gene, resulting in an arg121-to-ter (R121X) substitution. The mutations were identified by whole-exome sequencing, and the parents were shown to be carriers. Functional studies were not performed.
In a Pakistani patient (patient E-1), born to consanguineous parents, with BDV syndrome (BDVS; 619326), Bosch et al. (2021) identified homozygosity for a 1-bp deletion (c.994del, NM_001873.3) in exon 6 of the CPE gene, resulting in a frameshift and premature termination (Ser333AlafsTer22). The mutation was found by whole-exome sequencing, and the parents were shown to be carriers. Functional studies were not performed.
Alsters, S. I. M., Goldstone, A. P., Buxton, J. L., Zekavati, A., Sosinsky, A., Yiorkas, A. M., Holder, S., Klaber, R. E., Bridges, N., van Haelst, M. M., le Roux, C. W., Walley, A. J., Walters, R. G., Meuller, M., Blakemore, A. I. F. Truncating homozygous mutation of carboxypeptidase E (CPE) in a morbidly obese female with type 2 diabetes mellitus, intellectual disability and hypogonadotrophic hypogonadism. PLoS One 10: e0131417, 2015. Note: Electronic Article. [PubMed: 26120850] [Full Text: https://doi.org/10.1371/journal.pone.0131417]
Bosch, E., Hebebrand, M., Popp, B., Penger, T., Behring, B., Cox, H., Towner, S., Kraus, C., Wilson, W. G., Khan, S., Krumbiegel, M., Ekici, A. B., Uebe, S., Trollmann, R., Woelfle, J., Reis, A., Vasileiou, G. BDV syndrome: an emerging syndrome with profound obesity and neurodevelopmental delay resembling Prader-Willi syndrome. J. Clin. Endocr. Metab. 106: 3413-3427, 2021. [PubMed: 34383079] [Full Text: https://doi.org/10.1210/clinem/dgab592]
Carrel, D., Du, Y., Komlos, D., Hadzimichalis, N. M., Kwon, M., Wang, B., Brzustowicz, L. M., Firestein, B. L. NOS1AP regulates dendrite patterning of hippocampal neurons through a carboxypeptidase E-mediated pathway. J. Neurosci. 29: 8248-8258, 2009. [PubMed: 19553464] [Full Text: https://doi.org/10.1523/JNEUROSCI.5287-08.2009]
Chen, H., Jawahar, S., Qian, Y., Duong, Q., Chan, G., Parker, A., Meyer, J. M., Moore, K. J., Chayen, S., Gross, D. J., Glaser, B., Permutt, M. A., Fricker, L. D. Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum. Mutat. 18: 120-131, 2001. [PubMed: 11462236] [Full Text: https://doi.org/10.1002/humu.1161]
Cool, D. R., Normant, E., Shen, F., Chen, H.-C., Pannell, L., Zhang, Y., Loh, Y. P. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88: 73-83, 1997. [PubMed: 9019408] [Full Text: https://doi.org/10.1016/s0092-8674(00)81860-7]
Durmaz, A., Aykut, A., Atik, T., Ozen, S., Emecen, D. A., Ata, A., Isik, E., Goksen, D., Cogulu, O., Ozkinay, F. A new cause of obesity syndrome associated with a mutation in the carboxypeptidase gene detected in three siblings with obesity, intellectual disability and hypogonadotropic hypogonadism. J. Clin. Res. Pediat. Endocr. 13: 52-60, 2020. [PubMed: 32936766] [Full Text: https://doi.org/10.4274/jcrpe.galenos.2020.2020.0101]
Hall, C., Manser, E., Spurr, N. K., Lim, L. Assignment of the human carboxypeptidase E (CPE) gene to chromosome 4. Genomics 15: 461-463, 1993. [PubMed: 8449522] [Full Text: https://doi.org/10.1006/geno.1993.1093]
Manser, E., Fernandez, D., Loo, L., Goh, P. Y., Monfries, C., Hall, C., Lim, L. Human carboxypeptidase E: isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro. Biochem. J. 267: 517-525, 1990. [PubMed: 2334405] [Full Text: https://doi.org/10.1042/bj2670517]
Naggert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., Leiter, E. H. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10: 135-142, 1995. [PubMed: 7663508] [Full Text: https://doi.org/10.1038/ng0695-135]
Plum, L., Lin, H. V., Dutia, R., Tanaka, J., Aizawa, K. S., Matsumoto, M., Kim, A. J., Cawley, N. X., Paik, J.-H., Loh, Y. P., DePinho, R. A., Wardlaw, S. L., Accili, D. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nature Med. 15: 1195-1201, 2009. [PubMed: 19767734] [Full Text: https://doi.org/10.1038/nm.2026]