PLCG2-associated antibody deficiency and immune dysregulation – PLCG2 gene.


Antibody deficiency and immune dysregulation associated with PLCG2 (PLAID), also known as cold atypical family urticaria or type 3 cold autoinflammatory family syndrome, is an immune system process characterized by the development of urticaria when the skin is exposed to temperatures cold

In addition to urticaria, affected individuals may have a burning sensation in the throat when eating cold foods. Prolonged exposure to cold can lead to loss of consciousness or a serious allergic reaction known as anaphylaxis. Some affected individuals develop granuloma at the tip of the nose, ears and fingers shortly after birth, which can subsequently extend to the dorsal thorax and extremities. Other signs and symptoms may include reduced immune system function, which results in recurrent infections such as colds, ear infections or episodes of pneumonia; autoimmune thyroiditis; and vitíligo. Most people with PLAID have abnormal blood antibodies known as ANA (Antinuclear antibodies).

This process is due to mutations in the PLCG2 gene (phospholipase C gamma 2), located on the long arm of chromosome 16 (16q23.3), which encodes the enzyme phospholipase C gamma 2 (PLCγ2). This enzyme performs a chemical reaction that allows molecules to transmit signals that direct cellular functions, including growth, maturation and migration. The PLCγ2 enzyme is particularly important in immune system cells, including B cells, NK cells and mast cells. The enzyme is critical to recognize and fight against foreign invaders, such as bacteria and viruses. When invaders are detected, the PLCγ2 enzyme transmits signals for B cells to produce immunoglobulins. Signaling through the enzyme is also involved in the destruction of foreign invaders by NK cells. The signaling of the PLCγ2 enzyme in mast cells and other immune cells triggers inflammation, which helps eliminate infections or other irritants. Mast cells also play a role in allergic reactions, which occur when the immune system overreacts to stimuli that are not harmful.

At least three mutations have been described in the PLCG2 gene that lead to the development of this process. The identified mutations are classified as germline mutations, which means that they are essentially present in all body cells and eliminate small segments of DNA from the PLCG2 gene. These changes alter a region of the PLCγ2 enzyme that controls whether the enzyme is activated or inactive. As a consequence, the altered PLCγ2 enzyme does not work properly. At low temperatures, the enzyme is constantly activated, even when it is not necessary. The signals activated by PLCγ2 in response to cold, particularly in mast cells in the skin, are likely to cause urticaria and other skin rashes. The deterioration resulting from the function of B cells and NK cells prevents the body from effectively fighting invaders, which causes recurrent infections in people with PLAID.

This process is inherited with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the process. In most cases, an affected person has a parent with the condition.

Tests performed in IVAMI: in IVAMI we detect mutations associated with antibody deficiency and immune deregulation associated with PLCG2 (PLAID), by means of complete PCR amplification of exons of the PLCG2 gene, and subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).