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The Spectrum of ELANE Mutations and their Implications in Severe Congenital and Cyclic Neutropenia
Author(s) -
Germeshausen Manuela,
Deerberg Sabine,
Peter Yvonne,
Reimer Christina,
Kratz Christian P.,
Ballmaier Matthias
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22308
Subject(s) - congenital neutropenia , biology , mutation , cyclic neutropenia , neutropenia , cancer research , neutrophil elastase , hematopoietic stem cell transplantation , immunology , genetics , gene , stem cell , inflammation , chemotherapy
Neutrophil elastase gene ( ELANE ) mutations are responsible for the majority of cases of severe congenital neutropenia ( CN ) and cyclic neutropenia ( C y N ). We screened CN ( n = 395) or C y N ( n = 92) patients for ELANE mutations and investigated the impact of mutations on m RNA expression, protein expression, and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) C y N patients, 69 of them were novel. C y N ‐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 / C y N 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 C y N , 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.