Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in ELA2, the gene encoding neutrophil elastase (NE), cause the human diseases cyclic neutropenia (CN) and severe congenital neutropenia (SCN). Numerous mutations are known, but their lack of consistent biochemical effect has proven puzzling. The recent finding that mutation of AP3B1, which encodes the beta subunit of adaptor protein complex 3 (AP3), is the cause of canine CN suggests a model for the molecular basis of hereditary neutropenias, involving the mistrafficking of NE: AP3 recognizes NE as a cargo protein, and their interaction implies that NE is a transmembrane protein. Computerized algorithms predict two NE transmembrane domains. Most CN mutations fall within predicted transmembrane domains and lead to excessive deposition of NE in granules, whereas SCN mutations usually disrupt the AP3 recognition sequence, resulting in excessive transport to the plasma membrane.
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PMID:Hereditary neutropenia: dogs explain human neutrophil elastase mutations. 1505 7

Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic neutropenia and severe congenital neutropenia (SCN). Genetic evaluation of other forms of neutropenia in humans and model organisms has helped to illuminate the role of NE. A canine form of cyclic neutropenia corresponds to human Hermansky-Pudlak syndrome type 2 (HPS2) and results from mutations in AP3B1 encoding a subunit of a complex involved in the subcellular trafficking of vesicular cargo proteins (among which NE appears to be one). Rare cases of SCN are attributable to mutations in the transcriptional repressor Gfi1 (among whose regulatory targets also include ELA2). The ultimate biochemical consequences of the mutations are not yet known, however. Gene targeting of ELA2 has thus far failed to recapitulate neutropenia in mice. The cycling phenomenon and origins of leukemic transformation in SCN remain puzzling. Nevertheless, mutations in all 3 genes are capable of causing the mislocalization of NE and may also induce the unfolded protein response, suggesting that there might a convergent pathogenic mechanism focusing on NE.
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PMID:Neutrophil elastase in cyclic and severe congenital neutropenia. 1705 55

Hermansky-Pudlak type 2 is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding disorders, recurrent infections, and moderate/severe neutropenia. The disease is caused by mutations in the AP3B1 gene encoding for the beta3A subunit of the adaptor protein 3 (AP-3) complex. Because the expression of the beta3A subunit is normally ubiquitous, its deficiency leads to a precise phenotype in cells with a large number of intracellular granules, such as neutrophils, natural killer cells, cytotoxic T lymphocytes, platelets, and melanocytes. Given the AP-3 deficiency, the lysosomal membrane proteins are not appropriately sorted to the granules but are delivered to plasma membrane with subsequent effects on cell development and differentiation. Missorting of proteins (eg, tyrosinase) in melanocytes and platelets accounts for oculocutaneous albinism and bleeding disorders, respectively. Absence of AP-3 leads to low intracellular content of neutrophil elastase and consequently to neutropenia. Abnormal movement of lytic granules and reduced perforin content in cytotoxic T lymphocytes and natural killer cells account for their respective defects in cytolytic activity. It is likely that the investigation of the physiopathology of Hermansky-Pudlak type 2 syndrome will reveal nonredundant functions of this adaptor protein in the intracellular trafficking of membrane proteins.
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PMID:Novel insights from adaptor protein 3 complex deficiency. 1793 56