The X-linked forms of mutations of CD154 affect the folding and stability of the molecule and cause severe immunodeficiency (known as hyper-IgM syndrome) with the manifestations of increased IgM and low or absence of IgG, IgA and IgE in serum [114,115,116], presentations also found in mice with deficiency of CD154 by gene targeting [117,118]. Here, IGHE is linked to immunodeficiency disease.