Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia

• Published in: Human mutation 2007-09, Vol.28 (9), p.874-881
• Main Authors: Salipante, Stephen J., Benson, Kathleen F., Luty, Joanna, Hadavi, Valeh, Kariminejad, Roxana, Kariminejad, Mohamad H., Rezaei, Nima, Horwitz, Marshall S.
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; de novo mutation; ELA2; Humans; Infant; Leukocyte Elastase - genetics; Leukocyte Elastase - metabolism; Male; Mutation; neutropenia; Neutropenia - congenital; Neutropenia - genetics; neutrophil elastase; Periodicity; Protein Folding; Protein Processing, Post-Translational - genetics; Protein Transport; Rats; Tissue Distribution; Transfection
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.20529

Heterozygous mutations of ELA2, encoding the protease neutrophil elastase (NE), cause either autosomal dominant cyclic neutropenia or severe congenital neutropenia (SCN). Three hypotheses have been proposed for how allelic mutations produce these different disorders: 1) disruption of proteolytic activity; 2) mislocalization of the protein; or 3) destabilization of the protein resulting in induction of the unfolded protein response. As with other dominant diseases with reduced reproductive fitness, sporadic cases can result from new mutations not inherited from either parent. Here we report an exceptional genetic phenomenon in which both a cyclic neutropenia patient and an SCN patient each possess two new ELA2 mutations. Because of the rarity of the phenomenon, we investigated the origins of the mutations and found that both arise nonmosaically and in cis from the paternally‐inherited allele. Moreover, these cases offer a unique opportunity to investigate molecular pathways distinguishing these two forms of hereditary neutropenia. We have characterized the mutants separately and in combination, with respect to their effects on proteolysis, subcellular trafficking, and induction of the unfolded protein response. Each pair of mutations acts more or less additively to produce equivalent net effects on reducing proteolytic activity and induction of the unfolded protein response, yet each has different and somewhat opposing effects on disturbing subcellular localization, thus offering support for a role for protein mistrafficking as a disease mechanism. Hum Mutat 28(9), 874–881, 2007. Published 2007 Wiley‐Liss, Inc.