Congruence with current disease hypotheses. A schematic of ELANE is shown. Mutations that inactivate the translation initiation codon and the Kozak sequence force translation to initiate from downstream in-frame ATG codons, resulting in amino-terminally truncated NE that lacks an ER-localizing presignal sequence, as well as a pro-zymogen sequence ordinarily restraining proteolytic activity prior to its removal. A second group of mutations may activate an IRES, also leading to translation of the internal ORFs. A third type of mutation, we speculate, may cause protein misfolding which activates an ER stress response and promotes IRES utilization, thereby indirectly also leading to translation of the internal ORFs. Catalytic triad of his, asp, and ser residues and amino terminal sequences ordinarily cleaved from the mature enzyme (dotted line) are shown.