ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology

Abstract

The 2 main forms of hereditary neutropenia are cyclic (CN) and severe congenital (SCN) neutropenia. CN is an autosomal dominant disorder in which neutrophil counts fluctuate with 21-day periodicity. SCN consists of static neutropenia, with promyelocytic maturation arrest in the bone marrow. Unlike CN, SCN displays frequent acquisition of somatic mutations in the gene CSF3R. CN is caused by heterozygous mutations in the gene ELANE, encoding neutrophil elastase. SCN is genetically heterogeneous but is most frequently associated with ELANE mutations. We discuss how the mutations provide clues into the pathogenesis of neutropenia and describe current hypotheses for its molecular mechanisms.

Figure 1

Schematic of mutations of ELANE associated with SCN and cyclic neutropenia. Amino acids listed in white represent the catalytic triad active site. Mutations in red are primarily associated with cyclic neutropenia but some have also been reported in SCN.