ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Abstract

There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.

Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

“…Individuals with SCN have myeloid hypoplasia with arrest of myelopoiesis at the promyelocyte/myelocyte stage (2). Current treatment by administration of high-dose granulocyte CSF (G-CSF) induces an increase in the neutrophil counts in the peripheral blood (PB) of most SCN patients.…”

Game of clones: the genomic evolution of severe congenital neutropenia

“…5 Although the genetic evidence that ELANE mutations are causative to SCN and CyN is compelling, it is far from clear how they contribute to the chronic or cyclic episodes of severe neutropenia. 6,7 Initially it was thought that the ELANE mutations in CyN were distinct from, and more "benign" than, those found in SCN mutations. However, later studies in extended patient series showed that, although there are trends in the spectrum of ELANE mutations toward either SCN or CyN, there is also a significant overlap.…”

“…Postulated mechanisms include: (1) altered function through mutant NE mislocalization (ie, granular versus membrane-proximal); (2) altered biochemical properties affecting substrate specificities of the mutant NE; and (3) protein misfolding in the endoplasmic reticulum (ER), triggering an unfolded protein response (UPR). 7 Given the mutation diversity, none of these potential explanations can be held responsible for causing neutropenia in all patients. Complicating matters even further, SCN patients have been reported in which ELANE expression in the myeloid progenitors (promyelocyte, myelocytes, metamyelocytes) is severely down-regulated, casting doubts on whether the mutant NE protein contributed at all to the neutropenia in these cases.…”

Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder

“…19 Neutrophil elastase is also a potent activator of eosinophils. 20 Since neutrophil cycling was observed in all four subjects with definite EAE and preceded the eosinophilia in two subjects, the coding regions of ELANE were sequenced using DNA from three subjects and two normal controls.…”