Submitted November 7, 2007
Accepted March 3, 2008
Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations
Manuela Germeshausen, Magda Grudzien, Cornelia Zeidler, Hengameh Abdollahpour, Sevgi Yetgin, Nima Rezaei, Matthias Ballmaier, Bodo Grimbacher, Karl Welte*, and Christoph Klein
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Department of Clinical Immunology, University Hospital Freiburg, Freiburg, Germany
Department of Pediatric Hematology, Hacettepe University, Children's Hospital, Ankara, Turkey
Immunology, Asthma and Allergy Research Institute, University of Tehran, Tehran, Iran, Islamic Republic of
Department of Immunology and Molecular Pathology, Royal Free Hospital & University College Medical School, London, United Kingdom
* Corresponding author; email: welte.karl.h{at}mh-hannover.de.
Homozygous mutations in HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN) (Nat Gen 39:86, 2007). By screening 88 patients with CN we identified six additional patients with HAX1 mutations carrying four novel mutations. Two of these affect both published transcript variants of HAX1, the other two mutations only affect transcript variant 1. Analysis of the patients' genotype and phenotype revealed a striking correlation: Mutations affecting transcript variant 1 only were associated with CN (23/23 patients), whereas mutations affecting both transcript variants caused CN and neurological symptoms including epilepsy and neuro-developmental delay (6/6 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.
