Hepoxilin A 3 (HXA 3 ) synthase deficiency is causative of a novel ichthyosis form

Non‐bullous congenital ichthyosis erythroderma (NCIE) and lamellar ichthyosis (LI) are characterized by mutations in 12 R ‐lipoxygenase (12 R ‐LOX) and/or epidermal lipoxygenase 3 (eLOX3) enzymes. The eLOX3 lacks oxygenase activity, but is capable of forming hepoxilin‐type products from arachidonic acid‐derived hydroperoxide from 12 R ‐LOX, termed 12 R ‐hydroperoxyeicosa‐5,8,10,14‐tetraenoic acid (12 R ‐HpETE). Mutations in either of two enzymes lead to NCIE or LI. Moreover, 12 R ‐LOX‐deficient mice exhibit severe phenotypic water barrier dysfunctions. Here, we demonstrate that 12 R ‐HpETE can also be transformed to 8 R ‐HXA 3 by hepoxilin A 3 (HXA 3 ) synthase (12‐lipoxygenase), which exhibits oxygenase activity. We also presented a novel form of ichthyosis in a patient, termed hepoxilin A 3 synthase‐linked ichthyosis (HXALI), whose scales expressed high levels of 12 R ‐LOX, but were deficient of HXA 3 synthase.