Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 Mutations

Boxer, Laurence A.; Stein, Steven; Buckley, Danielle; Bolyard, Audrey Anna; Dale, David C.

doi:10.1016/j.jpeds.2005.12.029

Cited by 48 publications

(32 citation statements)

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“…The patients with the S97L ELA2 mutation have been previously described. 20 All patients with SCN were treated with G-CSF at the time of bone marrow harvest. These studies were approved by the human studies committee at Washington University.…”

Section: Human Bone Marrow Samplesmentioning

confidence: 99%

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

Grenda

Murakami

Ghatak

et al. 2007

Blood

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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. IntroductionSevere congenital neutropenia (SCN) is a rare disorder characterized by severe neutropenia present at birth, an arrest of granulocytic differentiation at the promyelocyte or myelocyte stage, and a marked propensity to develop acute myeloid leukemia and myelodysplasia. 1,2 Cyclic neutropenia (CN) is a related disorder of granulopoiesis, characterized by periodic oscillations in the numbers of circulating neutrophils and other peripheral blood cells. 3 Mutations of the ELA2 gene encoding neutrophil elastase (NE) have been identified in nearly all patients with CN and in approximately 50% of cases of SCN. [4][5][6][7][8][9] To date, more than 50 distinct mutations of the ELA2 gene have been reported in patients with CN or SCN. [5][6][7]10 Most of the mutations (ϳ80%) are missense mutations, although mutations that lead to splicing defects (ϳ10%) and premature stop codons (ϳ10%) also have been observed. With a few exceptions, specific ELA2 mutations are associated with SCN or CN, but not both, suggesting a genotypephenotype correlation.The molecular mechanisms by which ELA2 mutations disrupt granulopoiesis are unclear. Genetic studies provide 2 important clues. First, in all cases, the ELA2 mutations are heterozygous, [5][6][7] suggesting a dominant mechanism of action. Second, a case report of paternal mosaicism for an ELA2 mutation provides evidence that expression of mutant NE inhibits granulopoiesis in a cell intrinsic fashion, since no toxic paracrine effects of mutant NE protein on wild-type granulocytic cells in this mosaic individual were observed. 11 NE is a serine protease expressed at extremely high levels at the promyelocyte stage of granulocytic differentiation. 12 However, an extensive in vitro biochemical characterization of a l...

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Section: Human Bone Marrow Samplesmentioning

confidence: 99%

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

Grenda

Murakami

Ghatak

et al. 2007

Blood

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175

155

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“…More than 200 different ELANE mutations have been identified, randomly distributed over all exons as well as in introns 3 and 4 22,23,24 . There is a substantial overlap in the mutations causing severe congenital neutropenia and those causing cyclic neutropenia, revealing that genotyping alone is not sufficient to establish a clinical diagnosis [23][24][25][26] . Some ELANE mutations, such as p.C151Y or p.G214R, cause a more-severe phenotype in terms of increased risk of leukemogenesis, poor G-CSF response, and risk of severe infections 16 .…”

Section: Mortalitymentioning

confidence: 99%

Severe congenital neutropenias

2017

Nat Rev Dis Primers

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Severe congenital neutropenias are a heterogeneous group of rare haematological diseases that are characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenetic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte-colony stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients.Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination, and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (e.g. trisomy 21, monosomy 7) as well as somatic pre-leukaemic mutations are recommended. Graphical abstractCorrespondence to: K.W., karl.welte@med.uni-tuebingen.de.

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“…Recently, Boxer and co-workers published compelling data supporting autosomal dominant transmission of ELA2 mutations as cause for SCN. Five unrelated children, all affected by severe congenital neutropenia, were found to be descendents of a single sperm donor carrying an ELA2 mutation, whose semen was used to impregnate five healthy mothers [5]. A few patients with mosaicism have also been reported [6,7].…”

Section: Severe Congenital Neutropeniamentioning

confidence: 99%

Genetic Insights into Congenital Neutropenia

Klein

Welte

2009

Clinic Rev Allerg Immunol

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Congenital neutropenia syndromes comprise a heterogeneous group of disorders leading to increased susceptibility to bacterial infections. Recent work has elucidated the molecular basis of several congenital neutropenia syndromes such as mutations in ELA2, HAX1, GF11, and WAS. In addition, a number of complex clinical syndromes associating congenital neutropenia have been recognized and elucidated on a genetic level, e.g. p14-deficiency or G6PC3-deficiency. The clinical and genetic findings of various neutropenia syndromes are being discussed.

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Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 Mutations

Cited by 48 publications

References 9 publications

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

Severe congenital neutropenias

Genetic Insights into Congenital Neutropenia

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