NLRP1 gene

Last updated on: 02.12.2023

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The NLRP1 gene (NLRP1 stands for: NLR Family Pyrin Domain Containing 1) is a protein-coding gene located on chromosome 17p13. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene, but the biological significance of some variants has not been determined. An important paralog of this gene is NLRP3.

General information
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The NLRP1 gene encodes a protein of the same name, NLRP1 protein, a cytosolic protein which, like other NLRPs, is one of the key mediators of programmed cell death. The NLRP1 protein interacts with caspase 1 and to a lesser extent with caspase 9. The interleukins interleukin-1β and interleukin-18 as well as a lytic form of cell death (pyroptosis/necroptosis) are processed via this activation pathway. NLRP1 is activated by numerous microbial stimuli (Bacillus anthracis lethal toxin, Toxoplasma gondii, muramyl dipeptides, viral proteins (?).

Clinical picture
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Several autoinflammatory diseases with skin manifestations have been described in which germline-activating mutations in the inflammasome sensor NLRP1 are present.

These include:

  • Multiple self-healing palmoplantar carcinoma (MSPC): In this, there are gains of function in the pyrin domain of NLRP1 (Zhong FL et al. (2016). Clinically, ulcerated, hyperkeratotic nodules (keratoacanthomas) appear, predominantly on the palmoplantar skin as well as on the conjunctiva and corneal epithelium. These lesions usually regress spontaneously, but can predispose to the development of squamous cell carcinoma, making a link between inflammasome and carcinogenesis evident.
  • Familial keratosis lichenoides chronica
  • NLRP1-associated autoinflammation with arthritis and dyskeratosis(NAIAD): Another Mendelian autoinflammatory disorder associated with mutations in the NLRP1 gene (c.2176C>T; p.Arg726Trp) is NAIAD- also known as AIADK (NLRP1-associated autoinflammation with arthritis and dyskeratosis) (Grandemange S et al. 2017).
  • Furthermore, NLRP1 polymorphisms in the NLRP1 gene are associated with:
    • a familial form of vitiligo - VAMAS1 - vitiligo-associated multiple autoimmune disease susceptibility (Levandowski CB et al. 2013)
    • NAIAD (NLRP1- associated autoinflammation with arthritis)

    • JRRP (juvenile-onset recurrent respiratory papillomatosis)

    • Psoriasis

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  1. Grandemange S et al. (2017) A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis 76:1191-1198.
  2. Levandowski CB et al. (2013) NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A. 110:2952-2956.
  3. Męcińska-Jundziłł K et al. (2023) Evaluation of polymorphisms and expression of PTPN22, NLRP1 and TYR genes in vitiligo patients. Postepy Dermatol Alergol 40:225-233.
  4. Sureja NP et al. (2022) Autoinflammation with Arthritis and Dyskeratosis an Inflammasomopathy. Case Report and Review of Literature. Indian Journal of Rheumatology 1: 65-68
  5. Zhong FL et al. (2016) Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell 167:187-202.e17.

Last updated on: 02.12.2023