ABCA12 – autosomal recessive congenital ichthyosis

ABCA12 encodes an ATP-binding cassette lipid transporter critical for keratinocyte lamellar granule function and skin barrier integrity. Pathogenic biallelic variants in ABCA12 underlie autosomal recessive congenital ichthyosis (ARCI), encompassing phenotypes such as lamellar ichthyosis and congenital ichthyosiform erythroderma. Disruption of ABCA12 impairs lipid secretion in the stratum corneum, leading to hyperkeratotic scaling and compromised barrier function.

Genetic analyses across multiple cohorts confirm autosomal recessive inheritance, with segregation observed in 5 affected relatives homozygous for the recurrent c.4676G>T (p.Gly1559Val) variant in a consanguineous family (5 probands; PMID:22257947). In a Scandinavian screening of 132 ARCI patients, ABCA12 mutations were detected in 8 unrelated cases, highlighting variant heterogeneity and occasional founder alleles (PMID:27025581). The spectrum includes missense, splice, and loss-of-function changes, with missense variants generally associated with milder CIE or lamellar phenotypes and truncating alleles causing more severe presentations.

One representative variant, c.4676G>T (p.Gly1559Val), affects the first nucleotide-binding domain and segregates fully with disease status in multiple families. This missense change has been reported in homozygous form in 5 individuals with non-bullous congenital ichthyosiform erythroderma, underscoring its clinical relevance.

Functional studies demonstrate that ABCA12 localizes to lamellar granules in normal epidermis, whereas truncating mutations lead to congested lipid secretion in cultured keratinocytes. Corrective gene transfer of wild-type ABCA12 restores lipid transport and lamellar granule function in patient cells, providing direct evidence of pathogenicity and a basis for potential gene therapy approaches (PMID:16007253).

No conflicting reports dispute the association; all studies consistently link ABCA12 loss to ARCI phenotypes. Combined genetic and functional evidence confirms that ABCA12 deficiency is causative for ARCI across diverse ethnic groups.

Key Take-home: ABCA12 genetic testing should be incorporated into ARCI diagnostic panels, and functional assays of lipid transport may aid variant interpretation and therapeutic development.

References

• European journal of dermatology • 2012 • Non-bullous congentital ichthyosiform erythroderma associated with homozygosity for a novel missense mutation in an ATP binding domain of ABCA12. PMID:22257947
• Acta dermato-venereologica • 2016 • Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia: Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients. PMID:27025581
• The Journal of clinical investigation • 2005 • Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. PMID:16007253

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