Contract grant sponsor: Federal Ministry of Education and Research (German Network on Congenital Bone Marrow Failure Syndromes).
The Spectrum of ELANE Mutations and their Implications in Severe Congenital and Cyclic Neutropenia
Article first published online: 2 APR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 6, pages 905–914, June 2013
How to Cite
Germeshausen, M., Deerberg, S., Peter, Y., Reimer, C., Kratz, C. P. and Ballmaier, M. (2013), The Spectrum of ELANE Mutations and their Implications in Severe Congenital and Cyclic Neutropenia. Hum. Mutat., 34: 905–914. doi: 10.1002/humu.22308
Communicated by George P. Patrinos
- Issue published online: 20 MAY 2013
- Article first published online: 2 APR 2013
- Accepted manuscript online: 5 MAR 2013 10:26AM EST
- Manuscript Accepted: 27 FEB 2013
- Manuscript Received: 27 OCT 2012
- Federal Ministry of Education and Research
- severe congenital neutropenia;
- cyclic neutropenia;
Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital neutropenia (CN) and cyclic neutropenia (CyN). We screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations and investigated the impact of mutations on mRNA expression, protein expression, and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel. CyN-associated mutations were predicted to be more benign than CN-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R mutations, malignant transformation, and the need for hematopoietic stem cell transplantation was significantly higher in CN patients with ELANE mutation than in ELANE mutation negative patients. Cellular elastase activity was reduced in neutrophils from CN/CyN patients, irrespective of the mutation status. In CN, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wild-type ELANE. Despite differences in the spectrum of mutations in CN or CyN, type or localization of mutation only partially determine the clinical phenotype. Specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation.