Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) are sporadic or inherited hematologic disorders of myelopoiesis. Heterozygous mutations in the gene encoding neutrophil elastase (ELA2) have been reported in both diseases. We used an inducible system to express a panel of ELA2 mutations and found for almost all mutants disruption of intracellular neutrophil elastase (HNE) protein processing at different levels. This disruption resulted in cytoplasmic accumulation of a nonfunctional protein, thereby preventing its physiologic transport to azurophil granules. Furthermore, the secretory capacity of the mutant proteins was greatly diminished, indicating alteration of the regulated and the constitutive pathways. Through analysis of primary granulocytes from SCN patients carrying ELA2 mutations, we found an identical pattern of intracellular accumulation of mutant HNE protein in the cytoplasm. Moreover, cells expressing mutant HNE protein exhibited a significant increase in apoptosis associated with up-regulation of the master ER chaperone BiP, indicating that disturbance of intracellular trafficking results in activation of the mammalian unfolded protein response.
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PMID:Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. 1655 67

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the production of misfolded NE protein, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Expression of mutant NE but not wild-type NE strongly induced BiP/GRP78 mRNA expression and XBP1 mRNA splicing, 2 classic markers of the UPR. The magnitude of UPR activation by a specific ELA2 mutation correlated with its associated clinical phenotype. Consistent with the UPR model, expression of mutant NE in primary human granulocytic precursors increased expression of CHOP (DDITS) and induced apoptosis in a protease-independent fashion. Most strikingly, UPR activation and decreased NE protein expression were detected in primary granulocytic precursors from SCN patients. Collectively, these data provide strong support for a UPR model of SCN disease pathogenesis and place SCN in a growing list of human diseases caused by misfolded proteins.
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PMID:Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. 1776 33