NIPAL4

NIPAL4, also known as ichthyin, is a human gene that encodes a member of the NIPA-like (NIPAL) family of transmembrane proteins. The encoded protein is predicted to function as a membrane transporter and is expressed in epidermal keratinocytes, with notable presence in the outer layers of the skin.

Function and role: While the precise substrate and transport mechanism for NIPAL4 are not fully established, the protein is believed to participate in lipid handling or transport processes integral to the formation and maintenance of the stratum corneum. Disruption of NIPAL4 function is associated with defective epidermal barrier formation and abnormal skin differentiation, contributing to ichthyosis.

Clinical significance: Pathogenic variants in NIPAL4 cause autosomal recessive congenital ichthyosis (ARCI). Affected individuals typically present with generalized dry, scaling skin from birth or early infancy, with substantial variability in severity. The phenotype reflects impaired skin barrier and altered lipid processing in the stratum corneum.

Genetics and diagnosis: NIPAL4 mutations show autosomal recessive inheritance. Genetic testing for NIPAL4 can confirm a diagnosis in individuals with ARCI features, and testing of family members may be offered for carrier status. Management is supportive and focused on maintaining skin hydration and reducing scaling, using emollients, keratolytics, and other dermatologic therapies as needed.

Research: Studies continue to delineate NIPAL4’s exact substrates and transport role, its interaction with other ARCI-associated genes, and potential avenues for targeted therapy.