title: Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.
abstract: Patients with autosomal dominant (AD), sporadic and X-linked severe congenital neutropenia (SCN) may have mutations in the elastase 2 (ELA2) or Wiskott-Aldrich syndrome (WAS) genes. Homozygous mutations in the HAX1 gene have recently been reported in autosomal recessive (AR) cases of primarily Middle-Eastern descent and the original Kostmann family. We screened 109 predominantly Caucasian SCN kindreds for mutations in these genes; 33 (30%) had 24 different ELA2 mutations, five of them novel, two kindreds (2%) had WAS mutations and four kindreds (4%) had three different HAX1 mutations, two of them novel. One HAX1 mutation (p.Ser43LeufsX11) was found in an AR Ashkenazi Jewish kindred, the other (p.Glu31LysfsX54) in two unrelated British patients with sporadic disease. Microsatellite analysis of the HAX1 locus revealed a common haplotype (maximum distance 4.1 Megabases) for the p.Glu31LysfsX54 patients, suggesting a possible ancestral founder. In functional assays, the level of spontaneous and staurosporine-induced apoptosis was increased in neutrophils from both p.Ser43LeufsX11 patients but not a p.Glu31LysfsX54 patient, suggesting the possible presence of modifying factors. The low incidence of HAX1 mutations in our study suggests that the frequency may vary between racial groups but suggests that irrespective of inheritance or racial origin, SCN patients should be screened for HAX1 mutations.
authors.affiliation: Department of Haematology, University College London, London, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.forename: Phil J
authors.initials: PJ
authors.lastname: Ancliff
authors.forename: Arnold
authors.initials: A
authors.lastname: Pizzey
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C104759:HAX1 protein, human; D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D012697:Serine Endopeptidases; C117309:pancreatic elastase II