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PASLI disease
PASLI disease is a rare genetic disorder of the immune system. PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood. These include bacterial infections of the respiratory system and chronic viremia due to Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV). Individuals with PASLI disease also have an increased risk of EBV-associated lymphoma. Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition which they called Activated PI3K Delta Syndrome (APDS).
==Genetics and Function==
PASLI disease is caused by gain-of-function mutations in the gene ''PIK3CD'', which stands for phosphatidylinositol 3-kinase, catalytic, delta.〔(【引用サイトリンク】url=http://www.omim.org/entry/602839 )〕 ''PIK3CD'' maps to human chromosome 1p36.2 and encodes the p110δ catalytic PI(3)K subunit. The p110δ subunit is a protein of 1,044 amino acids that is predominantly expressed in leukocytes and plays a role in adaptive immunity. PI(3)K enzymes are activated by a variety of cell surface receptors including antigen receptors on lymphocytes. Once activated, they phosphorylate inositol lipids in the cell membrane, which triggers additional downstream signaling events.
A variant of PASLI disease can all be caused by heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8+ T cells toward terminally differentiated, senescent effector cells with short telomeres.
P110δ contains at least five domains (figure 1): adaptor-binding domain, a Ras GTPase-binding domain, a PI(3)K-type C2 domain, helical domain, and a kinase domain.〔 Mutations have been identified in multiple domains,〔 although there seems to be a recurrent transition mutation (G>A causing E1021K) in the C lobe of the kinase domain,〔〔 leading to constitutive activation of enzyme function. Specific p110δ mutants cause stronger binding to membranes and relieve inhibition of the kinase by regulatory proteins.〔〔 These changes appear to affect the immune system through over activating the downstream mTOR pathway.〔
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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