Cellular and Metabolic Basis for the Ichthyotic Phenotype in NIPAL4 (Ichthyin)–Deficient Canines

Abstract

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with 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 NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

Biology, diagnosis and treatment of Malassezia dermatitis in dogs and cats Clinical Consensus Guidelines of the World Association for Veterinary Dermatology

“…Diseases of dogs characterized histopathologicaly by parakeratotic hyperkeratosis – such as zinc‐responsive dermatosis and hepatocutaneous syndrome/superficial necrolytic dermatitis – have been anecdotally reported to promote yeast overgrowth (Section 10). The presence of Malassezia overgrowth is associated with pruritus in American bulldogs with autosomal recessive congenital ichthyosis caused by a single base deletion in the gene NIPAL4 . In cats, a histological study of 550 skin biopsy cases identified Malassezia overgrowth most commonly with thymoma‐associated dermatosis (TAD) and paraneoplastic alopecia (PNA) associated with internal neoplasia .…”

Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4

“…All ARCI genes encode proteins that are involved in the formation of the cornified lipid envelope (CLE) and many of them, including NIPAL4, in the synthesis of fatty acids and ceramides (Hirabayashi, Murakami, & Kihara, ; Mauldin et al, ). There is increasing evidence that NIPAL4 works as an Mg 2+ transporter for FATP4, an acyl‐CoA synthetase, which is considered important for the generation of ω‐hydroxy ultra‐long chain fatty acid‐CoA which is involved in the epidermal lipid metabolism (Li, Vahlquist, & Törmä, ; Mauldin et al, ).…”

“…All ARCI genes encode proteins that are involved in the formation of the cornified lipid envelope (CLE) and many of them, including NIPAL4, in the synthesis of fatty acids and ceramides (Hirabayashi, Murakami, & Kihara, ; Mauldin et al, ). There is increasing evidence that NIPAL4 works as an Mg 2+ transporter for FATP4, an acyl‐CoA synthetase, which is considered important for the generation of ω‐hydroxy ultra‐long chain fatty acid‐CoA which is involved in the epidermal lipid metabolism (Li, Vahlquist, & Törmä, ; Mauldin et al, ). The resulting accumulation of long‐chain free fatty acids (FFAs) in NIPAL4 deficient skin is assumed to trigger membrane stripping and disruption of organelle membranes (Mauldin et al, ), which disturbs overall metabolic and intracellular membrane component processing and eventually the transport of components for the formation of lamellar bilayers to the extracellular space by lamellar bodies.…”

“…There is increasing evidence that NIPAL4 works as an Mg 2+ transporter for FATP4, an acyl‐CoA synthetase, which is considered important for the generation of ω‐hydroxy ultra‐long chain fatty acid‐CoA which is involved in the epidermal lipid metabolism (Li, Vahlquist, & Törmä, ; Mauldin et al, ). The resulting accumulation of long‐chain free fatty acids (FFAs) in NIPAL4 deficient skin is assumed to trigger membrane stripping and disruption of organelle membranes (Mauldin et al, ), which disturbs overall metabolic and intracellular membrane component processing and eventually the transport of components for the formation of lamellar bilayers to the extracellular space by lamellar bodies. This may explain specific epidermal ultrastructural abnormalities identified in patients with ARCI having mutations in NIPAL4 , formerly classified as ARCI EM type III, which is characterized by deposition of complex or empty vesicles and perinuclear elongated membranes in granular layer cells (Arnold, Anton‐Lamprecht, Melz‐Rothfuss, & Hartschuh, ; Dahlqvist et al, ).…”

“…In addition to these cytotoxic events by putatively accumulating FFAs, NIPAL4 deficiency should lead to a lack of sphingolipid end products, resulting in a disturbed formation of the CLE. These two mechanisms may explain the impairment of the epidermal permeability barrier in patients with ARCI and thereby cause the observed clinical phenotype (Mauldin et al, ).…”