Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.

Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Research Abstract Details 

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Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Abstract Text:

David S Grenda,Mark Murakami,Jhuma Ghatak,Jun Xia,Laurence A Boxer,David Dale,Mary C Dinauer,Daniel C Link,David S Grenda,Mark Murakami,Jhuma Ghatak,Jun Xia,Laurence A Boxer,David Dale,Mary C Dinauer,Daniel C Link,David S Grenda,Mark Murakami,Jhuma Ghatak,Jun Xia,Laurence A Boxer,David Dale,Mary C Dinauer,Daniel C Link,

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.

Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Publishing Authors By Initials

DS Grenda,M Murakami,J Ghatak,J Xia,LA Boxer,D Dale,MC Dinauer,DC Link,DS Grenda,M Murakami,J Ghatak,J Xia,LA Boxer,D Dale,MC Dinauer,DC Link,DS Grenda,M Murakami,J Ghatak,J Xia,LA Boxer,D Dale,MC Dinauer,DC Link,

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Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Blood

VOLUME: 110

Page Numbers: 4179-87

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 30

MONTH: 08

YEAR: 2007

Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Information

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LANGUAGE: eng

NlmUniqueID: 7603509

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Grant and Affiliation Information for Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.

AFFILIATION: Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: T32 HL07088-23

ACRONYM: HL

MEDLINETA: Blood

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