|
LRBA deficiency is a rare genetic disorder of the immune system. This disorder is caused by a mutation in the gene ''LRBA''. LRBA stands for “Lipopolysaccharide (LPS)-responsive vesicle trafficking, beach- and anchor-containing” gene. This condition is characterized by autoimmunity, lymphoproliferation, and immune deficiency. It was first described by Gabriela Lopez-Herrera from University College London in 2012. Investigators in the laboratory of (Dr. Michael Lenardo ) at National Institute of Allergy and Infectious Diseases, the National Institutes of Health and (Dr. Michael Jordan ) at Cincinnati Children’s Hospital Medical Center later described this condition and therapy in 2015. ==Genetics and function== LRBA deficiency is caused by biallelic loss-of-function mutations in the gene ''LRBA''. LRBA maps to human chromosome 4q31.3, has 58 exons, and encodes for one of the largest intracellular proteins, LRBA.〔 The LRBA 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 LRBA mutations decrease or eradicate LRBA protein in patients with this disorder.〔 Although the function of LRBA is not fully understood, it is hypothesized 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 LRBA deficiency sufficiently impairs post-translational CTLA4 expression, as the abundance of CTLA4 protein in patients is significantly lower than normal. It is also believed that LRBA may bind to the cytoplasmic tail of CTLA4 in order to guide the endosome to the activated receptor complex that aids in the secretion of CTLA4. By binding to the tail, LRBA also may protect and regulate the degradation of CTLA4 by blocking the binding of AP-1. AP-1 is the protein complex responsible for trafficking CTLA4 to lysosomes for degradation.〔 ==Inheritance== LRBA deficiency 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 LRBA deficiency have often involved homozygosity via consanguinity or geographically isolated communities. Parents of child with LRBA deficiency 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 ''LRBA''. Children who inherit only one abnormal copy of ''LRBA'' will not develop LRBA deficiency although they may have affected children, particularly if they marry within the family. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「LRBA deficiency」の詳細全文を読む スポンサード リンク
|