Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

The Netherlands
Congenital neutropenia with ELA-2 mutations (ELA2-CN): Identification of (epi)genetic co-factors and molecular pathways underlying clinical heterogeneity

Project Coordinator

Hannover Medical School Molecular Hematopoiesis


Cornelia Zeidler Hannover Medical School Molecular Hematopoiesis Hannover, Germany
Deniz Yilmaz Karapinar Ege University Faculty of Medicine Childrens Hospital Department of Pediatric Hematology Bomova-Izmir, Turkey
Hannah Tamary Schneider Children's Medical Center of Israel Pediatric Hematology Petah Tikva, Israel
Ivo Touw Erasmus University Medical Center Hematology Office H EE13-30c Rotterdam, The Netherlands
Paul J. Coffer University Medical Center Molecular Immunology Lab Department of Immunology & Pediatrics Ultrech, The Netherlands

Publications of the ELA2-CN project

Major results of the project

Congenital neutropenia includes a heterogeneous group of serious but rare inherited disorders associated with chronic neutropenia (permanent=CN or cyclic=CyN). To date, the majority of patients suffering from a congenital type of neutropenia can be genetically characterized. The genes are transmitted either by autosomal dominant or autosomal recessive inheritance in different genes. Sporadic mutations may also occur.
Congenital neutropenia patients with ELANE mutations (former gene name: ELA2) and cyclic neutropenia patients harbouring ELANE mutations (ELANE-CyN) represent approx. 60% of inherited neutropenia patients in Europe and North America. Other genetic defects causing CN like HAX1-, G6PC3-mutations have been identified in minor cohorts of consanguineous families in Europe only. Although both, the phenotype of CN and CyN, are related to identical ELANE mutations, the clinical course differs significantly: ELANE-CN patients have a high risk for secondary leukaemias (up to 20%), require higher G-CSF doses and develop G-CSF receptor mutations and have generally a constant neutrophil count, whereas ELANE-CyN patients respond to lower G-CSF doses without malignant transformation and present with the typical cycling of neutrophil counts throughout their life.
The aim of this E-Rare project was to exchange information and biomaterial on all patients suffering from ELANE-CN or ELANE-CyN and to perform genotype/phenotype correlation of patients suffering from congenital and cyclic neutropenia.

Genotype-phenotype correlation
We have collected clinical data on 96 ELANE-CN and 36 ELANE-CyN patients for genotype/phenotype correlation within our network.
Modifying genes
In samples from patients with ELANE-CN who developed leukaemia we have identified Runx1- and ASXL1 mutations in the leukemic cell sample of these patients.
Molecular pathways
We found significantly elevated phospho-STAT5 levels in CN-ELANE patients compared to CyNELANE patients and healthy individuals. We could show that hyperactivated STAT5 induces ubiquitination and degradation of LEF-1 protein. We were also able to show that bortezomib is able to inhibit LEF1 degradation. We plan to study other proteins involved in STAT5 activation, e.g. cbl, SHIP, SOCS3.
We also analysed the effects of different ELANE mutations on Nampt/NAD+/SIRT activation and deacetylation of p53 and FOXO3a and found substantial deacetylation and subsequent deactivation of these proteins.
ELANE induced pathomechanisms
We compared the effects of ELANE gene mutations, which are specific for CN, with ELANE mutations common for both, CN and CyN patients, on the induction of UPR, (BiP and ATF6 target genes). We found elevated expression levels of ATF6 and ATF6 target genes in cells transduced with ELANE-CN mutations, in comparison to ELANE-CN/CyN mutations.
Epigenetic alterations
To identify epigenetic alterations or passenger mutations in addition to ELANE mutations we performed whole genome sequencing a) in one family with two patients with congenital neutropenia (Father, Mother, Sister, two affected CN patients) and b) in one family of a patient with cyclic neutropenia (father, mother, brother, cyclic patient). So far we have detected sporadic nonsense mutations in the genes GRM1 and ACAP2 in one CN patient and an inherited mutation in TNFRSF1A in a CyN patient. The validation of these genes is in progress.

E-Rare 2012 - Created by Toussaint Biger