title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.
abstract: 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.
authors: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. germeshausen.manuela@mh-hannover.de
authors: Manuela
authors: M
authors: Germeshausen
authors: Sabine
authors: S
authors: Deerberg
authors: Yvonne
authors: Y
authors: Peter
authors: Christina
authors: C
authors: Reimer
authors: Christian P
authors: CP
authors: Kratz
authors: Matthias
authors: M
authors: Ballmaier
mesh_terms: D018387:Codon, Initiator; D004789:Enzyme Activation; D005091:Exons; D015870:Gene Expression; D005838:Genotype; D019337:Hematologic Neoplasms / Q000209:etiology; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009503:Neutropenia / Q000150:complications / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018387:Codon, Initiator; D022821:RNA Splice Sites; D012333:RNA, Messenger; D019272:Leukocyte Elastase