Recent advances in understanding inherited disorders of keratinization

Mutations in KDSR cause recessive progressive symmetric erythrokeratoderma and thrombocytopenia

In 2017, Boyden et al. reported that mutations in KDSR (3-ketodihydrosphingosine reductase) led to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum—also known as periorificial and ptychotropic erythrokeratoderma (PERIOPTER) syndrome¹⁰—characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, scaly skin on the hands and feet¹¹. Immunohistochemistry and yeast complementation studies have demonstrated that these mutations cause defects in KDSR function. Systemic isotretinoin therapy achieved nearly complete resolution in the two probands in whom it had been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

KDSR mutations have been implicated in the pathobiology of hereditary palmoplantar keratodermas and ichthyosis¹¹; another recent study has demonstrated the important role that KDSR plays in platelet biology¹². KDSR encodes KDSR, which catalyzes the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS), a key step in the ceramide synthesis pathway. The role of ceramides in platelet function is less understood, but the most likely pathomechanism for the thrombocytopenia is diminished sphingosine-1-phosphate (S1P) synthesis. This signaling lipid has been shown to promote platelet shedding from megakaryocytes¹³, and other studies have demonstrated that exogenous S1P and ceramides can restore platelet secretion and aggregation in knockout mice deficient in S1P and ceramides^14,15. While KDSR mutations block de novo ceramide biosynthesis, retinoids induce the salvage pathway for ceramide synthesis, providing pathogenesis-directed therapy of skin disease in some subjects.

Mutations in PNPLA1 cause autosomal recessive congenital ichthyosis by disrupting acylceramide biosynthesis

In 2012, Grall et al. found that mutations in the patatin-like phospholipase domain-containing protein 1 (PNPLA1) gene cause ARCI in dogs and humans via a positional cloning approach¹⁶. The phenotypic spectrum of PNPLA1 mutations is broad and can include a collodion membrane at birth; mature phenotypes can include fine or plate-like scale and erythema that can range from minimal to severe¹⁷.

Recent studies in cell-based and in vitro assays have shown that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, catalyzing ω-O-esterification with linoleic acid to produce acylceramide¹⁸. In PNPLA1 knockout mice, loss of ω-O-acylceramides in the stratum corneum results in a defective CLE and a disorganized extracellular lipid matrix^19–21. The administration of topical acylceramide on the skin of PNPLA1-deficient mice was shown to rebuild the CLE, partially rescuing the ichthyosis phenotype^19,21.

Mutations in SDR9C7 cause autosomal recessive congenital ichthyosis

In 2016, Shigehara et al. described a homozygous missense mutation in short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) underlying ARCI in three consanguineous Lebanese families and showed that SDR9C7 is expressed in the granular and cornified layers of the epidermis²². The pathomechanism of ichthyosis caused by SDR9C7 deficiency has been debated. Shigehara et al. cited prior evidence of SDR9C7 converting retinal into retinol²³, suggesting that the ichthyosis phenotype results from a vitamin A deficiency impairing epidermal differentiation²². Takeichi et al. noted reduced lipid contents and defective intercellular lipid layers in the stratum corneum on electron microscopy and postulated that the pathomechanism of the ichthyosis phenotype in SDR9C7 deficiency involves defective synthesis and metabolism of keratinocyte lipid contents²⁴.

Mutations in ELOVL1 cause neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features

In 2018, Kutkowska-Kaźmierczak et al. described a dominant missense mutation in elongation of very long chain fatty acids (VLCFAs)-like 1 (ELOVL1) in two kindreds that resulted in a syndrome of ichthyotic keratoderma, spasticity, mild hypomyelination, and dysmorphic features²⁵. Like ELOVL4, ELOVL1 is involved in fatty acid elongation, catalyzing the synthesis of saturated and mono-unsaturated VLCFAs²⁶. ELOVL1 activity has also been shown to be regulated with the ceramide synthase CERS2, which is essential for C24 sphingolipid synthesis²⁷. A prior murine model deficient in Elovl1 demonstrated wrinkled, shiny, red skin, and electron microscopy showed diminished lipid lamellae in the stratum corneum. Thin-layer chromatography revealed decreased levels of ceramides with ≥C₂₆ fatty acids²⁸. Kutkowska-Kaźmierczak et al. suggest that the disease may result from the shortage of VLCFAs due to the lack of activity of mutated enzymes and speculate that the mutation may have a greater impact on VLCFA levels in the brain and skin than in fibroblasts or plasma²⁵.