ABCA12 – Congenital Non-bullous Ichthyosiform Erythroderma

Autosomal recessive congenital ichthyosis (ARCI) encompasses a spectrum of keratinization disorders, among which congenital non-bullous ichthyosiform erythroderma (CIE) is characterized by fine, whitish scales on erythematous skin. Biallelic pathogenic variants in the ATP-binding cassette transporter gene ABCA12 (HGNC:14637) disrupt lipid transport in lamellar granules, leading to a defective intercellular lipid barrier in the stratum corneum and resulting in the CIE phenotype (MONDO:0019306).

Genetic evidence supports an autosomal recessive inheritance mode with high penetrance. A large consanguineous Pakistani family exhibited five affected individuals homozygous for the missense variant c.4676G>T (p.Gly1559Val) in the first nucleotide-binding domain of ABCA12, segregating with disease ([PMID:22257947]). Across studies, at least 20 unrelated CIE probands have been reported with biallelic ABCA12 variants, including missense and splice-site changes, confirming a consistent genotype-phenotype correlation.

Variant spectrum in CIE is enriched for non-truncating alleles: missense substitutions and splicing defects in critical functional domains. Recurrent missense variants include p.Asn1380Ser and p.Thr1434Ala, often occurring in compound heterozygosity. A review of 66 ARCI families identified eight CIE pedigrees with ABCA12 mutations, of which ≥62.5% are predicted to produce truncated proteins but CIE typically involves ≥1 missense allele ([PMID:20672373]).

Functional studies demonstrate that ABCA12 localizes to keratinocyte lamellar granules and mediates glucosylceramide transport. Loss-of-function mutations lead to lipid secretion defects in patient-derived keratinocytes, which can be rescued by corrective gene transfer of ABCA12 ([PMID:16007253]). Mouse knockout models corroborate a critical role for ABCA12 in skin barrier formation and homeostasis.

Integration of genetic segregation, variant spectrum, and functional assays yields a Strong gene–disease association. ABCA12 testing should be included in diagnostic panels for ARCI and CIE, facilitating accurate prognostication, genetic counseling, and prenatal diagnosis. Further genotype-phenotype studies will refine variant pathogenicity assessments and tailor therapeutic strategies.

Key take-home: Biallelic ABCA12 variants cause autosomal recessive CIE by disrupting lipid transport in lamellar granules, and molecular diagnosis informs patient management and family planning.

References

• European Journal of Dermatology • 2012 • Non-bullous congenital ichthyosiform erythroderma associated with homozygosity for a novel missense mutation in an ATP binding domain of ABCA12 PMID:22257947
• Human Mutation • 2010 • ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts PMID:20672373
• 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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