1. ¹Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
2. ²School of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
3. ³Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA
4. ⁴Ludwig Institute of Cancer Research, University of California San Diego School of Medicine, La Jolla, CA, USA
5. ⁵Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
6. ⁶Department of Cellular and Molecular Medicine and Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA
7. ⁷Division of Rheumatology, Allergy, and Immunology, University of California San Diego School of Medicine, La Jolla, CA, USA

Correspondence: Dr HM Hoffman, Division of Rheumatology, Allergy, and Immunology, University of California San Diego, Mail Code 0635, 9500 Gilman Drive, La Jolla, CA 92093-0635, USA. E-mail: hahoffman@ucsd.edu

Received 20 June 2008; Revised 24 July 2008; Accepted 24 July 2008; Published online 21 August 2008.

Abstract

Mutations in NLRP3 (CIAS1) are identified in a continuum of related inflammatory disorders, known as cryopyrinopathies since NLRP3 codes for the protein cryopyrin. Approximately 40% of patients with classic presentation lack mutations in the coding region of NLRP3 suggesting heterogeneity or epigenetic factors. Cryopyrin is a key regulator of proinflammatory cytokine release. Therefore, variations in the NLRP3 promoter sequence may have effects on disease state in patients with cryopyrinopathies and other inflammatory diseases. In this report, we confirmed three 5'-untranslated region splice forms with two separate transcriptional start sites, and identified potential promoter regions and six new DNA promoter variants. One variant is unique to a mutation negative cryopyrinopathy patient and increases in vitro gene expression. Additional studies can now be performed to further characterize the NLRP3 promoter and sequence variants, which will lead to better understanding of the regulation of NLRP3 expression and its role in disease.