Autosomal Dominant Lamellar Ichthyosis Due to a Missense Variant in the Gene NKPD1

J Invest Dermatol. 2024 Dec;144(12):2754-2763.e6. doi: 10.1016/j.jid.2024.03.041. Epub 2024 Apr 18.

Abstract

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 ASPRV1 was 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 NKPD1 gene 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. NKPD1 encodes 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 NKPD1 mRNA 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.

Keywords: Autosomal dominant lamellar ichthyosis; Mendelian cornification disorders; NTPases; Nonsyndromic autosomal dominant congenital ichthyosis; Whole-exome sequencing.

MeSH terms

  • Adult
  • Cell Differentiation / genetics
  • Ceramides / metabolism
  • Epidermis / pathology
  • Exome Sequencing*
  • Female
  • Humans
  • Ichthyosis, Lamellar* / genetics
  • Ichthyosis, Lamellar* / pathology
  • Keratinocytes / pathology
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree*

Substances

  • Ceramides