ABCA12 – autosomal recessive congenital ichthyosis 4B

Autosomal recessive congenital ichthyosis 4B (HI) is the most severe form of autosomal recessive congenital ichthyoses, characterized by thick, platelike hyperkeratotic scales, deep fissures, ectropion and eclabion, with high neonatal mortality. ABCA12 encodes an ATP‐binding cassette lipid transporter essential for lamellar granule formation and lipid secretion in the stratum corneum. Loss of ABCA12 function disrupts epidermal barrier integrity, leading to the harlequin phenotype.

Biallelic ABCA12 variants underlie HI, with autosomal recessive inheritance established through homozygosity mapping in five consanguineous families and identification of pathogenic mutations in 11 of 12 screened probands (PMID:15756637). Over 80 unrelated individuals have been reported with compound heterozygous or homozygous truncating and critical missense variants, exceeding the ClinGen genetic evidence cap (PMID:21339420).

The variant spectrum is dominated by frameshift and nonsense changes, including recurrent c.859C>T (p.Arg287Ter) and p.Gly1961Glu, with at least one non‐truncating allele often modulating severity toward CIE or LI phenotypes. Segregation in multiple families confirms co‐segregation of ABCA12 alleles with disease (5 affected relatives). Missense substitutions in ATP‐binding domains can produce milder phenotypes when paired with truncating alleles.

Functional studies show ABCA12 localizes to lamellar granules in keratinocytes, and loss of function impedes lipid export, causing glucosylceramide accumulation. Corrective ABCA12 gene transfer in patient keratinocytes restores lamellar granule lipid secretion (PMID:16007253). Mouse knockout models recapitulate barrier defects.

Genotype‐phenotype correlation is robust: homozygous or compound heterozygous truncating variants invariably cause HI, while at least one missense allele yields milder congenital ichthyosis. No substantive conflicting evidence has emerged; reports of pityriasis rubra pilaris–like or localized phenotypes highlight incomplete penetrance of mild alleles.

In summary, the ABCA12–HI association is definitive, supported by comprehensive genetic, segregation and functional concordance. ABCA12 variant analysis is clinically actionable for prenatal diagnosis, genetic counseling and potential gene therapy development.

References

• American Journal of Human Genetics • 2005 • Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. PMID:15756637
• The Journal of Clinical Investigation • 2005 • Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. PMID:16007253
• Archives of Dermatology • 2011 • Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. PMID:21339420
• Human Mutation • 2010 • ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. PMID:20672373

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