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The identification of monogenic causes for cornification disorders has enhanced our understanding of epidermal differentiation and skin barrier function. Autosomal dominant lamellar ichthyosis is a rare condition, and ASPRV1was the only gene linked to autosomal dominant lamellar ichthyosis to date. We identified a heterozygous variant (ENST00000686631.1:c.1372G>T, p.[Val458Phe]) in the NKPD1gene in 7 individuals from a 4-generation German pedigree with generalized lamellar ichthyosis by whole-exome sequencing. Segregation analysis confirmed its presence in affected individuals, resulting in a logarithm of the odds score of 3.31. NKPD1encodes the NKPD1 protein, implicated in the plasma membrane; its role in human disease is as yet unknown. Skin histology showed moderate acanthosis and compact orthohyperkeratosis, and the ultrastructure differed clearly from that in ASPRV1-autosomal dominant lamellar ichthyosis. Although NKPD1mRNA expression increased during keratinocyte differentiation, stratum corneum ceramides exhibited no significant changes. However, affected individuals showed an elevated ratio of protein-bound ceramides to omega-esterified ceramides. This highlights NKPD1's role in autosomal dominant lamellar ichthyosis, impacting ceramide metabolism and skin lipid barrier formation, as demonstrated through functional characterization.

Integrin α6β4, encoded by ITGA6and ITGB4, is a transmembrane component of hemidesmosomes and plays an important role in connecting keratinocytes with extracellular matrix proteins. ITGB4or ITGA6biallelic pathogenic variants cause junctional epidermolysis bullosa with pyloric atresia (JEB-PA), which is associated with high lethality. Patients that survive usually develop JEB of intermediate severity and uro-renal manifestations. Here, we report a very rare subtype of late-onset non-syndromic JEB associated with a recurrent amino acid substitution in the highly conserved cysteine-rich tandem repeats of the integrin β4 subunit. Literature review shows that among the patients diagnosed with ITGB4mutations, only two had no extracutaneous manifestations, and only two patients with JEB-PA carried missense mutations located in cysteine-rich tandem repeats. We analyzed the consequences of the novel variant ITGB4, c.1642G>A, p.Gly548Arg on the clinical phenotype, the predicted protein structure, cellular phenotype and gene expression pattern to demonstrate its pathogenicity. The results indicated that the p.Gly548Arg amino acid substitution affected the protein structure of integrin β4 subunits and disrupted the stability of hemidesmosomes, and in turn impaired the adhesion of keratinocytes. RNA-seq results indicated similar changes in “ECM structure organization” and “differentiation” in keratinocytes completely devoid of integrin β4 and with the amino acid substitution p.Gly548Arg, which further supports the dysregulation of the function of the integrin β4 subunit caused by p.Gly548Arg.