A functional analysis of pathogenic variants in NIPAL4 in patients with congenital ichthyosis

Background: Autosomal recessive congenital ichthyosis (ARCI) is a group of rare heterogeneous cornification disorders characterised by skin scaling and erythroderma. ARCI refers to harlequin ichthyosis and the lamellar ichthyosis/nonbullous congenital ichthyosiform erythroderma phenotypic spectrum. The aim of this study was to add to the understanding of structural consequences of NIPAL4 variants and the genotype/phenotype correlation.
Methods: SeqMan Ultra was used to analyse 196 ARCI patient samples from Central Europe for mutations in NIPAL4. Various in silico tools were used to predict pathogenicity and analyse protein structure.
Results: Pathogenic or likely pathogenic variants were found in around 11% of patients. Most patients had been diagnosed with lamellar ichthyosis, few of them with congenital ichthyosiform erythroderma. Scales were mostly small and fair or light brown in colour, texture was more superficial, and the scales did not form prominent ridges. Erythema was mild or not seen. Palmoplantar keratoderma was frequent, sometimes presenting with hyperlinearity. Crystal structures are not available; however, NIPAL4 isoform 1, but less so isoform 2, showed similarities with a drug transporter from Starkeya novella previously described with an outward-facing transmembrane topology. In contrast, NIPAL4 was predicted to have nine transmembrane domains, in line with 2D predictions. Most pathogenic variants were located in transmembrane regions and supposed to alter secondary structures and transport properties of NIPAL4.
Conclusion: This study further highlighted the genotype/ phenotype correlation in ARCI. It revealed structural consequences of NIPAL4 variants and paves the way to a functional understanding of the role of NIPAL4 deficiency