Hyper IgM, Immunodeficiency with hyper IgM type 3 (hyper-IgM Immunodeficiency With, type 3) - CD40 gene.

Immunodeficiency with hyper IgM type 3 (HIGM3) is a rare disorder characterized by normal or elevated levels of serum IgM with absence of IgG, IgA and IgE, which results in a profound susceptibility to bacterial infections. Other signs and symptoms may include breathlessness, hepatomegaly and developmental delay.

Immunodeficiency with hyper IgM type 3 (HIGM3) is due to mutations in the gene CD40, located on the long arm of chromosome 20 (20q12-q13.2). This gene is a member of the TNF receptor family. The encoded protein is a receptor on immune cells and is essential for mediation of a wide variety of immune and inflammatory responses including T cell response dependent switching immunoglobulin class, memory for the development of B cells and the formation of germinal centers. The adapter protein TNFR2 interacts with this receptor and serves as a mediator of signal transduction. The interaction of this receptor and its ligand is necessary for microglial activation induced by beta-amyloid. They described several variants of the alternatively spliced transcript of this gene encoding distinct isoforms.

They have identified several mutations in the CD40 gene in individuals with immunodeficiency with hyper IgM type 3. These mutations result in the loss of CD40 gene expression on the surface of B lymphocytes and monocytes. Mutations cause a faulty interaction with CD40 ligand, thereby preventing subsequent signaling. These mutations lead to the inability of B cells to undergo isotype switching, an inability to mount an immune response specific antibodies and lack of germinal center formation. An identified mutation leads to an amino acid substitution of cysteine for the amino acid arginine. Another identified mutation occurs in the CD40 gene in the splice site (IVS3-2A-T).

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with immunodeficiency with hyper IgM type 3 by the complete PCR amplification of the gene exons CD40, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).