NIPAL4 – Congenital Non-bullous Ichthyosiform Erythroderma

Biallelic variants in NIPAL4 underlie autosomal recessive congenital non-bullous ichthyosiform erythroderma (congenital non-bullous ichthyosiform erythroderma). Ichthyin, the NIPAL4‐encoded protein, is highly expressed in the granular layer of the epidermis and is critical for Mg2+-dependent lipid processing.

In a consanguineous Tunisian family, four patients were diagnosed with congenital ichthyosiform erythroderma and found to be homozygous for c.534G>T (p.Glu178Asp), a novel missense variant predicted by 3D modeling to shrink the transport channel of ichthyin (PMID:31876100).

A separate Tunisian kindred exhibited an erythrokeratodermia variabilis-like ARCI phenotype in two sisters, who were homozygous for p.Pro279Ala. In silico analyses forecast protein destabilization and disrupted Mg2+ transport, expanding the clinical spectrum to include EKV-like ARCI (PMID:34669720).

Early linkage studies in two consanguineous Pakistani families with autosomal recessive congenital ichthyosis—encompassing lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma—identified a recurrent p.Ala176Asp missense change, reinforcing NIPAL4 as an ARCI gene. NIPAL4 mRNA localized to the granular layer in patient epidermis (PMID:20016120).

Functional assays revealed that ichthyin interacts with the fatty acid transporter FATP4 in the stratum granulosum. Proximity ligation assays demonstrated reduced ichthyin–FATP4 interactions in ichthyin-deficient models and altered expression in NIPAL4 mutants, indicating a Mg2+-dependent lipid processing defect compromising the epidermal barrier (PMID:23290633).

These data support a loss-of-function mechanism for NIPAL4 missense variants leading to defective transmembrane channel architecture and impaired epidermal lipid transport. The consistent genotype–phenotype correlations across multiple families, coupled with functional concordance, affirm a Moderate level of clinical validity for the NIPAL4–congenital non-bullous ichthyosiform erythroderma association.

Key Take-home: Molecular diagnosis of NIPAL4 variants enables accurate genetic counseling and informs potential strategies to restore epidermal lipid barrier function.

References

• Molecular Genetics & Genomic Medicine • 2020 • Identification of a novel missense mutation in NIPAL4 gene: First 3D model construction predicted its pathogenicity. PMID:31876100
• PloS One • 2021 • Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis. PMID:34669720
• Dermatology (Basel, Switzerland) • 2010 • NIPAL4/ichthyin is expressed in the granular layer of human epidermis and mutated in two Pakistani families with autosomal recessive ichthyosis. PMID:20016120
• Journal of Dermatological Science • 2013 • Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis. PMID:23290633

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