Dominantly inherited severe congenital neutropenia

Briars, Graham; Parry, Hugh; Ansari, Bilal

doi:10.1016/s0163-4453(96)93081-9

Cited by 30 publications

(19 citation statements)

References 7 publications

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“…3,4 A few cases consistent with autosomal dominant inheritance have been identified. 5 CN is characterized by recurrent severe neutropenia (Ͻ 0.5 ϫ 10 9 /L) with a 21-day cycle. 6 Patients are susceptible to opportunistic infections during neutropenic periods.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register

Bellanné‐Chantelot

Clauin²,

Leblanc³

et al. 2004

Blood

184

148

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Section: Introductionmentioning

confidence: 99%

Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register

Bellanné‐Chantelot

Clauin²,

Leblanc³

et al. 2004

Blood

184

148

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“…[1][2][3][4] The observation that patients with SCN experience myeloid maturation arrest at the promyelocyte stage in the bone marrow has led to the suggestion that a defect in maturation or the premature death of developing myeloid cells, or both, contributes to the pathogenesis of the disease. Given that most patients respond to recombinant human granulocyte-colonystimulating factor (G-CSF) with increased ANC (usually more than 1.0 ϫ 10 9 /L), [5][6][7] myeloid maturation signaling appears intact.…”

Section: Introductionmentioning

confidence: 99%

Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes

Massullo

Druhan

Bunnell

et al. 2005

Blood

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Mutations in the ELA2 gene encoding neutrophil elastase (NE) are present in most patients with severe congenital neutropenia (SCN). However, the mechanisms by which these mutations cause neutropenia remain unknown. To investigate the effects of mutant NE expression on granulopoiesis, we used the HL-60 promyelocytic cell line retrovirally transduced with the G185R NE mutant that is associated with a severe SCN phenotype. We show that the mutant enzyme accelerates apoptosis of differentiating but not of proliferating cells. Using metabolic labeling, confocal immunofluorescence microscopy, and immunoblot analysis of subcellular fractions, we also demonstrate that the G185R mutant is abnormally processed and localizes predominantly to the nuclear and plasma membranes rather than to the cytoplasmic compartment observed with the wildtype (WT) enzyme. Expression of the G185R mutant appeared to alter the subcellular distribution and expression of adaptor protein 3 (AP3), which traffics proteins from the trans-Golgi apparatus to the endosome. These observations provide further insight into potential mechanisms by which NE mutations cause neutropenia and suggest that abnormal protein trafficking and accelerated apoptosis of differentiating myeloid cells contribute to the severe SCN phenotype resulting from the G185R mutation. (Blood. 2005;105:3397-3404)

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“…However, recent reports have emphasized autosomal-dominant inheritance [2]. Fever and serious bacterial infections are seen in a newborn with SCN, and the absolute neutrophil count (ANC) is usually less than 0.2 × 10 9 /L.…”

Section: Severe Congenital Neutropeniamentioning

confidence: 99%

Molecular basis and therapy of disorders associated with chronic neutropenia

Stein

Dale

2003

Curr Allergy Asthma Rep

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There have been many recent advances in our understanding of the molecular basis of neutropenia disorders, primarily through advances in genetic analysis of inherited disorders. Molecular and cellular studies now suggest that accelerated apoptosis of neutrophil precursors in the bone marrow is the common pathophysiologic mechanism. Severe congenital neutropenia and cyclic neutropenia, both usually inherited as autosomal-dominant disorders, are caused by mutations in the neutrophil elastase gene. Myelokathexis is attributed to the downregulation of the bcl-x protein, but the genetic basis is not yet known. The genes for several diseases with more complex phenotypes (eg, glycogen storage disease type 1b, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, dyskeratosis congenita, Griscelli syndrome, Barth syndrome, and Wiskott-Aldrich syndrome) have all been identified recently. The molecular mechanisms for most acquired disorders causing neutropenia (eg, idiopathic neutropenia, pure white-cell aplasia, myelodysplasia, and aplastic anemia) are not yet known. Granulocyte colony stimulating factor (G-CSF) is effective treatment for several of these conditions. Through better understanding of these disorders, we anticipate that better treatments will be found in the future.

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Dominantly inherited severe congenital neutropenia

Cited by 30 publications

References 7 publications

Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register

Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register

Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes

Molecular basis and therapy of disorders associated with chronic neutropenia

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