SNOMEDCT: 124493003, 234627009; DO: 0111583;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q24.2 | Carboxypeptidase N deficiency | 212070 | Autosomal recessive | 3 | CPN1 | 603103 |
A number sign (#) is used with this entry because of evidence that carboxypeptidase-N deficiency (CPND) is caused by homozygous or compound heterozygous mutation in the CPN1 gene (603103) on chromosome 10q24.
Carboxypeptidase-N deficiency (CPND) is an autosomal recessive disorder characterized by episodic angioedema, acute or chronic urticaria, asthma, and/or allergic hypersensitivities such as hay fever. Homozygous individuals as well as their heterozygous family members have levels of carboxypeptidase N that are below the reference range, and heterozygotes are symptomatic, albeit to a generally milder degree (Mathews et al., 1980; Vincent et al., 2024).
Carboxypeptidase N is a serum alpha globulin metalloenzyme that inactivates C3a, C4a, C5a, bradykinin, kallidin, and fibrinopeptides. Mathews et al. (1980) found a low level of this enzyme (21% of normal) in a 65-year-old man with an 11-year history of episodic angioedema occurring about 40 times a year. The attacks, which lasted about 24 hours, most often involved the face and tongue but sometimes involved larger areas of pruritic, red swellings on the trunk or limbs. The proband's affected sister, who had a history of angioedema of the lips, acute urticaria of unknown cause, and asthma, had an equally depressed level of enzyme activity. Six children of these 2 sibs had intermediate levels consistent with heterozygous status. Multiple members of the family had allergic manifestations, i.e., angioedema/chronic urticaria, hay fever/asthma, or both.
Vincent et al. (2024) reported 4 unrelated families (A, B, C, and D) with hereditary angioedema (HAE) and mutation in the CPN1 gene. The probands in families A and B presented with recurrent urticaria and peripheral angioedema, triggered in the family A proband after stimulation for in vitro fertilization, whereas onset in the family B proband occurred while she was on oral contraceptives. The proband in family C had recurrent urticaria and abdominal symptoms that were resistant to H1 antihistamines, and the proband in family D presented with cold urticaria and H1 antihistamine-resistant angioedema. All 4 families included relatives who experienced similar symptoms. An urticarial rash accompanied nearly 60% of symptomatic episodes of angioedema.
By sequencing the CPN1 gene in genomic DNA extracted from cells of the index patient reported by Mathews et al. (1980), Cao and Hegele (2003) demonstrated that the allergic manifestations in this family were due to presumed compound heterozygosity for 2 mutations in the CPN1 gene (see 603103.0001 and 603103.0002).
In the probands from 4 unrelated families with hereditary angioedema and urticaria, Vincent et al. (2024) identified biallelic mutations in the CPN1 gene. Probands B, C, and D were homozygous for the previously reported missense mutation G178D (603103.0002), whereas the proband in family A was compound heterozygous for G178D and a T245M substitution (603103.0003). Symptomatic family members who were tested were all heterozygous for the G178D mutation. Proband C and her affected mother and sister were also heterozygous for synonymous mutations in the CPN1 gene. In addition, symptomatic individuals in 3 of the families (A, B, and C) were reported to carry 1 or more variants in other kinin-associated genes; the relationship of the variants to the hereditary angioedema phenotypes in those families was unclear.
Cao, H., Hegele, R. A. DNA polymorphism and mutations in CPN1, including the genomic basis of carboxypeptidase N deficiency. J. Hum. Genet. 48: 20-22, 2003. [PubMed: 12560874] [Full Text: https://doi.org/10.1007/s100380300003]
Mathews, K. P., Curd, J. G., Hugli, T. E. Decreased synthesis of serum carboxypeptidase N (SCPN) in familial SCPN deficiency. J. Clin. Immun. 6: 87-92, 1986. [PubMed: 3958137] [Full Text: https://doi.org/10.1007/BF00915368]
Mathews, K. P., Pan, P. M., Gardner, N. J., Hugli, T. E. Familial carboxypeptidase N deficiency. Ann. Intern. Med. 93: 443-445, 1980. [PubMed: 7437116] [Full Text: https://doi.org/10.7326/0003-4819-93-3-443]
Mathews, K. P. Deficiencies in regulator proteins. 4. Anaphylatoxin inactivator. Prog. Allergy 39: 344-351, 1986. [PubMed: 3562474]
Vincent, D., Parsopoulou, F., Martin, L., Gaboriaud, C., Demongeot, J., Loules, G., Fischer, S., Cichon, S., Germenis, A. E., Ghannam, A., Drouet, C. Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency. J. Allergy Clin. Immun. Glob. 3: 100223, 2024. Note: Erratum: J. Allergy Clin. Immun. Glob. 3: 100319, 2024. [PubMed: 38445235] [Full Text: https://doi.org/10.1016/j.jacig.2024.100223]