Clinical Implications of Mutations of Neutrophil Elastase in Congenital and Cyclic Neutropenia

Dale, David C.; Liles, W. Conrad; Garwicz, Daniel; Aprikyan, Andrew A.G.

doi:10.1097/00043426-200105000-00005

Cited by 78 publications

(105 citation statements)

References 12 publications

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“…During the intervals of neutropenia, affected individuals are at risk for opportunistic infections [Dale and Hammond, 1988]. Both cyclic and congenital neutropenia (MIM] 202700) are caused by mutations in the ELA2 gene (MIM] 130130), which encodes the human neutrophil elastase (HNE) protein (SWISSPROT P08246) [Horwitz et al, 1999;Dale et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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“…1,2 It is often caused by mutations of the ELA2 gene [3][4][5] or, less frequently, of the GFI1 gene. 6 Other major complications are leukemia and the myelodysplastic syndrome (MDS), the latter affecting about 10% of patients.…”

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confidence: 99%

Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register

Ferry

Ouachée

Leblanc

et al. 2004

Bone Marrow Transplant

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“…3 Recently, a variety of mutations in the gene encoding the serine protease neutrophil elastase (ELA2) have been demonstrated in majority of patients with SCN (Aprikyan et al Blood 2000; 96: 445 (abstract)). 4 G-CSF-R mutation has been associated in most patients with ELA2 mutations that show evolution into leukemia. 5 Development of acute lymphoblastic leukemia (ALL) in patients with SCN has been extremely rare, and to our knowledge, only two cases who carried G-CSF-R gene mutations have been described.…”

Section: To the Editormentioning

confidence: 99%

Acute lymphoblastic leukemia in a patient with congenital neutropenia without G-CSF-R and ELA2 mutations

et al. 2005

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Clinical Implications of Mutations of Neutrophil Elastase in Congenital and Cyclic Neutropenia

Cited by 78 publications

References 12 publications

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register

Acute lymphoblastic leukemia in a patient with congenital neutropenia without G-CSF-R and ELA2 mutations

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