CAPS are caused by variants (also known as mutations) in the NLRP3 gene. The NLRP3 gene provides instructions for making a protein called cryopyrin. Cryopyrin is a member of a family of proteins called intracellular "NOD-like" receptor (NLR) proteins. These proteins are involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight foreign invaders and help repair damaged tissues. After this has been accomplished, the body stops (inhibits) the inflammatory response to prevent damage to its own cells and tissues. Cryopyrin is involved in the assembly of a molecular complex called an inflammasome, which helps trigger the inflammatory process.

Researchers believe that NLRP3 gene variants that cause CAPS result in an overactive cryopyrin protein, which leads to inappropriate inflammatory responses. Impairment of the body's mechanisms for controlling inflammation results in the episodes of fever and damage to the body's cells and tissues seen in CAPS.

Normal Function

The NLRP3 gene provides instructions for making a protein called cryopyrin. Cryopyrin is a member of a family of proteins called intracellular "NOD-like" receptor (NLR) proteins. Cryopyrin is found mainly in white blood cells and in cartilage-forming cells (chondrocytes).

NLR proteins are involved in the immune system, helping to start and regulate the immune system's response to injury, toxins, or foreign invaders. NLR proteins recognize specific molecules and respond by helping to turn on (activate) certain parts of the immune system. Cryopyrin recognizes bacteria; chemicals such as asbestos, silica, and uric acid crystals; and compounds released by injured cells.

Cryopyrin molecules assemble themselves, along with other proteins, into structures called inflammasomes, which help trigger the process of inflammation. Inflammation occurs when the immune system sends signaling molecules as well as white blood cells to a site of injury or disease to fight foreign invaders and help repair damaged tissues. Once the threat is over, the body stops (inhibits) the inflammatory response, to prevent damage to its own cells and tissues.

Health Conditions Related to Genetic Changes

Cryopyrin-associated periodic syndromes

Several variants (also known as mutations) in the NLRP3 gene have been found to cause cryopyrin-associated periodic syndromes (CAPS). CAPS are a group of conditions that have overlapping signs and symptoms. The conditions are generally characterized by periodic episodes of skin rash, fever, and joint pain. CAPS include three conditions known as familial cold autoinflammatory syndrome type 1 (FCAS1), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID). These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. FCAS1 is the least severe form of CAPS, MWS is intermediate in severity, and NOMID is the most severe form.

Many of the variants that cause CAPS are in a region of the NLRP3 gene known as exon 3. All of the variants likely result in the cryopyrin protein being overactive. Inflammasomes made with abnormal cryopyrin proteins trigger inflammatory responses even when there is no injury or disease. Impairment of the body's mechanisms for controlling inflammation results in episodes of fever and widespread damage to the body’s cells and tissues.

While the CAPS spectrum shares similar signs and symptoms, it is unclear why variants in different parts of the NLRP3 gene cause the patterns of features that distinguish FCAS1, MWS, and NOMID.

Other Names for This Gene

• AII/AVP
• AII/AVP receptor-like
• angiotensin/vasopressin receptor AII/AVP-like
• AVP
• C1orf7
• CIAS1
• CLR1.1
• cryopyrin
• NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3
• NACHT, LRR and PYD containing protein 3
• NALP3_HUMAN
• NLR family, pyrin domain containing 3
• nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3
• PYPAF1
• PYRIN-containing APAF1-like protein 1

Genomic Location

Learning disabilities, including expressive language disorders, are generally not reported as a feature of Muckle-Wells syndrome.

The gene responsible for Muckle-Wells syndrome, called NLRP3, is also responsible for related conditions including the less severe familial cold autoinflammatory syndrome and the more severe neonatal onset multisystem inflammatory disease (also called NOMID, or CINCA). These conditions are collectively called cryopyrin associated periodic syndromes (CAPS). Some authors have suggested that the signs and symptoms of people with NLRP3 gene mutations may overlap more than previously thought. The features that typically distinguish NOMID from the other conditions include chronic aseptic meningitis, which can result in severe developmental delay and disability. While people diagnosed with Muckle-Wells syndrome generally do not have chronic aseptic meningitis, mild features of NOMID have been reported in some people with Muckle-Wells syndrome.