<unk>  presents as a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. Predominant clinical problems include idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and an autoimmune enteropathy. Before the discovery of these gene mutations, patients were diagnosed with common variable immune deficiency (CVID), which is characterized by low antibody levels and recurrent infections. Infections mostly affect the respiratory tract, as many patients suffer from chronic lung disease, pneumonias, and bronchiectasis. Lymphocytic interstitial lung disease (ILD) is also observed, which complicates breathing and leads to impairment of lung function and mortality. Infections can also occur at other sites, such as the eyes, skin and gastrointestinal tract. Many patients suffer from chronic diarrhea and inflammatory bowel disease. Other clinical features can include hepatosplenomegaly, reoccurring warts, growth retardation, allergic dermatitis, and arthritis. Notably,<unk>  has also been associated with type 1 diabetes mellitus. There is significant clinical phenotypic overlap with disease caused by CTLA4 haploinsufficiency. Since<unk>  loss results in a loss of CTLA4 protein, the immune dysregulation syndrome of<unk>  deficient patients can be attributed to the secondary loss of CTLA4. Because the predominant features of the disease include autoantibody-mediated disease (AIHA, ITP), Treg defects (resembling those found in CTLA4 haploinsufficient patients), autoimmune infiltration (of non-lymphoid organs, also resembling that found in CTLA4 haploinsufficient patients), and enteropathy, the disease has been termed LATAIE for<unk>  with autoantibodies, Treg defects, autoimmune infiltration, and enteropathy. Genetics==<unk>  domain structures. Shown are the<unk>  mutations of nine patients.<unk>  is caused by biallelic loss-of-function mutations in the gene<unk> .<unk>  maps to human chromosome 4q31.3, has 58 exons, and encodes for one of the largest intracellular proteins,<unk> . The<unk>  protein belongs to a distinct sub-family of proteins characterized by a “beige and CHS”, or BEACH, domain followed by repeated WD40 domains at the carboxy terminus. These related BEACH-containing proteins have been found to regulate trafficking of intracellular vesicles. These loss-of-function<unk>  mutations decrease or eradicate<unk>  protein in patients with this disorder. Model depicting the regulation of CTLA4 vesicle trafficking by<unk>  Although the function of<unk>  is not fully understood, it was recently reported that this protein plays a major immuno-regulatory role in the expression, function, and trafficking of cytotoxic T lymphocyte-associated protein 4 (CTLA4). CTLA4 is an immune effector molecule that acts as an inhibitory checkpoint for the immune response. CTLA4 resides in intracellular vesicles, or endosomes, of regulatory T cells (Tregs) that are released and mobilize to the cell surface after T cell receptor stimulation. It is hypothesized that<unk>  sufficiently impairs post-translational CTLA4 expression, as the abundance of CTLA4 protein in patients is significantly lower than normal. Knockdown of<unk>  in wildtype cells, also leads to a post-translational loss of CTLA4 protein. Co-immunopreciptation studies suggest that<unk>  binds to the cytoplasmic tail of CTLA4. By binding to the tail,<unk>  may protect and regulate the degradation of CTLA4 by blocking its trafficking to lysosomes for degradation. Inheritance<unk>  is inherited in an autosomal recessive manner. In autosomal recessive inheritance, two copies of an abnormal gene must be present in order for the disease to develop. Typically, this means both parents of an affected child silently carry one abnormal gene. This also explains why reported cases of<unk>  have often involved homozygosity via consanguinity or geographically isolated communities. Parents of a child with<unk>  have a 25% chance of having another affected child with each pregnancy. This risk is independent of prior children’s status. For example, if the first two children in a family are affected, the next child has the same 25% risk of inheriting the mutation. All affected individuals have two abnormal copies of<unk> . Children who inherit only one abnormal copy of<unk>  will not develop<unk>  although they may have affected children, particularly if they marry within the family.
LRBA deficiency
NGLY1 deficiency
Adenosine deaminase 2 deficiency
WNT4 deficiency
Janus kinase 3 deficiency
PMM2 deficiency
Adenosine deaminase deficiency
GATA2 deficiency