Mutations in several lipid synthetic enzymes that block fatty acid (FA) and ceramide (Cer) production, that are critical for barrier formation, produce autosomal recessive congenital ichthyosis (ARCI), and associated abnormalities in permeability barrier homeostasis. Yet, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations among the most prevalent ARCI remains unknown. NIPAL4 could encode a protein that delivers Mg++, a co-factor required for the acylCoA synthetase moiety in FA transport protein 4 (FATP4), which is both mutated in ichthyosis prematurity syndrome (IPS), and as we show here, accompanied by similar ultrastructural abnormalities. Barrier function was abnormal in an index patient and in a pedigree of canines with NIPAL4 mutations. The barrier abnormality could be attributed to evident cytotoxicity, manifested as extensive membrane stripping, likely due to the known detergent effects of non-esterified free FFA. Cytotoxicity in turn compromised lamellar body secretion and formation of the corneocyte lipid envelope (CLE), as well as attenuation of the cornified envelope (CE), suggesting a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in ichthyin deficiency. Thus, ichthyin deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. Yet, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical acylCer, apparently due to ongoing accumulation of toxic metabolites, which likely further contribute to disease pathogenesis.
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