HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)

2006 ◽  
Vol 39 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Christoph Klein ◽  
Magda Grudzien ◽  
Giridharan Appaswamy ◽  
Manuela Germeshausen ◽  
Inga Sandrock ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Disease

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2645-2650 ◽  
Author(s):  
Phil J. Ancliff ◽  
Rosemary E. Gale ◽  
Ri Liesner ◽  
Ian M. Hann ◽  
David C. Linch
Keyword(s):  
Neutrophil Elastase ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Autosomal Recessive Disorder ◽  
Severe Neutropenia ◽  
Base Substitution ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Familial Form

Abstract Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

scholarly journals Hax1 regulates neutrophil adhesion and motility through RhoA

2011 ◽  
Vol 193 (3) ◽  
pp. 465-473 ◽  
Author(s):  
Peter J. Cavnar ◽  
Erwin Berthier ◽  
David J. Beebe ◽  
Anna Huttenlocher
Keyword(s):  
Adaptor Protein ◽  
Neutrophil Function ◽  
Negative Regulator ◽  
Neutrophil Adhesion ◽  
Severe Congenital Neutropenia ◽  
Loss Of Function ◽  
Congenital Neutropenia ◽  
Rhoa Activity ◽  
Protein X ◽  
Kostmann Disease

Kostmann disease is an inherited severe congenital neutropenia syndrome associated with loss-of-function mutations in an adaptor protein HS1-associated protein X-1 (Hax1). How Hax1 regulates neutrophil function remains largely unknown. In this paper, we use ribonucleic acid interference to deplete Hax1 in the neutrophil-like cell line PLB-985 and identify Hax1 as a negative regulator of integrin-mediated adhesion and chemotaxis. Using microfluidics, we show that depletion of Hax1 impairs neutrophil uropod detachment and directed migration. Hax1-deficient cells also display increased integrin-mediated adhesion and reduced RhoA activity. Moreover, depletion of RhoA induces increased neutrophil adhesion and impaired migration, suggesting that Hax1 regulates neutrophil adhesion and chemotaxis through RhoA. Accordingly, activation of RhoA is sufficient to rescue adhesion of Hax1-deficient neutrophils. Together, our findings identify Hax1 as a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA.

Ovarian failure in HAX1-deficient patients: is there a gender-specific difference in pubertal development in severe congenital neutropenia or Kostmann disease?

2012 ◽  
Vol 102 (1) ◽  
pp. 78-82 ◽  
Author(s):  
Göran Carlsson ◽  
Berit Kriström ◽  
Magnus Nordenskj˶ld ◽  
Jan-Inge Henter ◽  
Bengt Fadeel
Keyword(s):  
Pubertal Development ◽  
Ovarian Failure ◽  
Severe Congenital Neutropenia ◽  
Specific Difference ◽  
Congenital Neutropenia ◽  
Gender Specific ◽  
Kostmann Disease

A novel missense mutation in theHAX1gene in severe congenital neutropenia patients (Kostmann disease)

2009 ◽  
Vol 76 (6) ◽  
pp. 569-572 ◽  
Author(s):  
M Faiyaz-Ul-Haque ◽  
A Al-Jefri ◽  
HA Abalkhail ◽  
M Toulimat ◽  
MA Al-Muallimi ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Kostmann Disease
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