title: Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations.
abstract: Homozygous mutations in HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN). By screening 88 patients with CN, we identified 6 additional patients with HAX1 mutations carrying 4 novel mutations. Of these, 2 affect both published transcript variants of HAX1; the other 2 mutations affect only transcript variant 1. Analysis of the patients' genotypes and phenotypes revealed a striking correlation: Mutations affecting transcript variant 1 only were associated with CN (23 of 23 patients), whereas mutations affecting both transcript variants caused CN and neurologic symptoms, including epilepsy and neurodevelopmental delay (6 of 6 patients). In contrast to peripheral blood, transcript variant 2 was markedly expressed in human brain tissue. The clinical phenotype of HAX1 deficiency appears to depend on the localization of the mutation and their influence on the transcript variants. Therefore, our findings suggest that HAX1 isoforms may play a distinctive role in the neuronal system.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Magda
authors.initials: M
authors.lastname: Grudzien
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Hengameh
authors.initials: H
authors.lastname: Abdollahpour
authors.forename: Sevgi
authors.initials: S
authors.lastname: Yetgin
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D001923:Brain Chemistry; D002648:Child; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D050505:Mutant Proteins; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000208:ethnology / Q000235:genetics*; D010641:Phenotype; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D050505:Mutant Proteins; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger