Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations.
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.
Germeshausen
Manuela
M
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Grudzien
Magda
M
Zeidler
Cornelia
C
Abdollahpour
Hengameh
H
Yetgin
Sevgi
S
Rezaei
Nima
N
Ballmaier
Matthias
M
Grimbacher
Bodo
B
Welte
Karl
K
Klein
Christoph
C
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
D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D050505:Mutant Proteins; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger