IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.
Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.
Congenital insensitivity to pain with anhidrosis (CIPA), a rare and severe disorder, comprises absence of sensation to noxious stimuli, inability to sweat, and recurrent episodes of hyperthermia. It has a relatively high prevalence in the consanguineous Israeli-Bedouins. Clinical studies of 28 patients are reported here. Using the linkage analysis approach, we linked the disease in 9 of 10 unrelated Israeli-Bedouin families with CIPA to the TrkA gene, which encodes the receptor for nerve growth factor. In one family, linkage was excluded, implying that another gene, yet unidentified, is involved. Two new mutations in the tyrosine kinase domain of the TrkA gene were identified in our CIPA patients: a 1926-ins-T in most of the southern Israeli-Negev CIPA patients, and a Pro- 689-Leu mutation in a different isolate of Bedouins in northern Israel. Eight prenatal diagnoses were made in the southern Israeli-Negev Bedouins, two by linkage analysis and six by checking directly for the 1926-ins-T mutation. Three polymorphisms in the TrkA protein kinase encoding domain were also observed.
To evaluate the in vitro effect of meningococcal vaccination, 3 C7-deficient (C7-D) siblings and 2 normal controls were studied before and 6 weeks after vaccination with treatment meningococcal vaccine (serogroups A, C, Y, and W). Serobactericidal activity was not detected in the C7-D subjects and was low in the controls. Neither group was affected by vaccination. However, opsonized phagocytic killing increased significantly following vaccination in C7-D subjects and normal controls, despite only a modest increase in antimeningococcal titers. Heat inactivation of sera added to neutrophils resulted in low killing activity, which did not increase after vaccination. Thus, tetravalent meningococcal vaccine appears to enhance the phagocytic killing of meningococci in both normal and C7-deficient persons and should be given to all persons with C7 deficiencies.
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