NLRP12 Gene

Last updated on: 01.12.2023

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Definition
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The NLRP12 gene (NLRP12 stands for "NLR Family Pyrin Domain Containing 12") is a protein-coding gene located on chromosome 19q13.42. The NLRP12 gene encodes a member of the so-called CATERPILLER family (older name for NLR proteins) of cytoplasmic proteins.

A new class of (systemic) autoinflammatory syndromes (SAIDs) are referred to as NLRP12-associated diseases (NLRP12AD). The etiopathology of this special group of diseases is based on mutations in the NLRP12 gene. Excessive increases in IL-1beta secretion (80-175 fold) cause the inflammatory symptoms of the disease. In these patients, a dramatic improvement in symptoms can be achieved with Anakinra.

General information
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The encoded NLRP12 protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain and a C-terminal leucine-rich repeat region, acts as an anti-inflammatory factor by suppressing inflammatory reactions in activated monocytes.

Mutations in this gene, which cause a deficiency of the encoded protein, cause familial autoinflammatory cold syndrome type 2 (see below Familial cold urticaria).

Pathophysiology
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The encoded NLRP12 protein is mainly expressed in dendritic cells and macrophages and inhibits both canonical and non-canonical NF-kappa-B and ERK activation pathways. It acts as a negative regulator of NOD2 by driving its degradation via the proteasome pathway. In turn, the encoded protein promotes bacterial tolerance.

Furthermore, NLRP12 inhibits DDX58-mediated immune signaling against RNA viruses by reducing 'Lys-63'-linked DDX58 activation mediated by the E3 ubiquitin ligase TRIM25, but enhancing 'Lys-48'-linked DDX58 degradation mediated by the E3 ubiquitin ligase RNF125. Also acts as a negative regulator of the inflammatory response to mitigate obesity and obesity-associated diseases in adipose tissue.

Literature
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  1. Borghini S et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63: 830-839.
  2. Jeru I et al. (2008) Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Nat Acad Sci 105: 1614-1619.
  3. Jeru I et al. (2011) Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum 63: 1459-1464.
  4. Lich JD et al. (2007) CATERPILLER (NLR) family members as positive and negative regulators of inflammatory responses. Proc Am Thorac Soc 4:263-266.
  5. Shen M et al. (2017) NLRP12 autoinflammatory disease: a Chinese case series and literature review. Clin Rheum 36: 1661-1667.
  6. Vitale A et al. (2013) Rare NLRP12 variants associated with the NLRP12-autoinflammatory disorder phenotype: an Italian case series. Clin Exp Rheum 31: 155-156.
  7. Xia X et al. (2016) Identification of a novel NLRP12 nonsense mutation (Trp408X) in the e

Last updated on: 01.12.2023