NIPAL4 – Lamellar Ichthyosis

NIPAL4 encodes ichthyin, a putative magnesium transporter critical for epidermal lipid processing. Autosomal recessive mutations in NIPAL4 underlie lamellar ichthyosis (MONDO:0017778), characterized by large, polygonal scales and impaired skin barrier function. Patients often present at birth or early childhood with collodion membrane formation and subsequent generalized scaling without erythroderma.

Multiple case reports describe novel homozygous missense variants in NIPAL4. A Romanian family exhibited c.403A>C (p.Ser135Arg) with lamellar ichthyosis and dental enamel defects (PMID:26456858). A pediatric patient with LI carrying an unidentified novel NIPAL4 variant showed dramatic improvement with high-dose vitamin D therapy (PMID:38018299).

In multi-patient cohorts, a recurrent missense variant c.527C>A (p.Ala176Asp) segregated in two consanguineous Pakistani families with autosomal recessive congenital ichthyosis including LI (PMID:20016120). In a Turkish cohort of 12 LI patients, variants included c.2T>C (p.Met1Thr), c.341C>A (p.Ala114Asp), and c.527C>A (p.Ala176Asp) (PMID:24397709).

Further studies identified c.534G>T (p.Glu178Asp) in Tunisian CIE patients, with 3D modeling predicting channel constriction (PMID:31876100), and a novel c.835C>G (p.Pro279Ala) in EKV-like ARCI, expanding the phenotype (PMID:34669720).

Functional assays demonstrate high NIPAL4 mRNA expression in the stratum granulosum and physical interaction with FATP4, essential for lipid processing. Proximity ligation assays showed reduced ichthyin in FATP4-deficient skin and increased FATP4 in NIPAL4-mutant epidermis, supporting a key role in barrier integrity (PMID:23290633).

Collectively, at least 24 unrelated probands with homozygous or compound heterozygous missense variants, segregation in four families, and concordant functional data support a strong gene–disease relationship. Clinical testing of NIPAL4 informs diagnosis, prognosis, and potential targeted therapies such as vitamin D supplementation.

References

• Pediatric Dermatology • 2024 • Lamellar ichthyosis with a novel NIPAL4 variant showing dramatic response to high-dose vitamin D therapy. PMID:38018299
• 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
• Clinical and Experimental Dermatology • 2016 • Novel mutation in NIPAL4 in a Romanian family with autosomal recessive congenital ichthyosis. PMID:26456858
• Ophthalmic Genetics • 2015 • Genotype and Anterior Segment Phenotype in a Cohort of Turkish Patients with Lamellar Ichthyosis. PMID:24397709
• 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

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