ABCA12 – Lamellar Ichthyosis

ABCA12 encodes a keratinocyte lipid transporter localized to lamellar granules and is essential for intercellular lipid layer formation in the stratum corneum. Pathogenic biallelic variants in ABCA12 underlie autosomal recessive congenital ichthyosis subtypes, including Lamellar ichthyosis. Clinical presentations of lamellar ichthyosis feature large, dark, polygonal scales without significant erythroderma and often a history of collodion membrane at birth.

Genetic evidence for the ABCA12–lamellar ichthyosis association is robust. A review of genotype–phenotype correlations identified 56 distinct ABCA12 mutations in 66 unrelated autosomal recessive congenital ichthyosis families, of which 10 families presented with lamellar ichthyosis (PMID:20672373). In a consanguineous Pakistani kindred, five siblings homozygous for c.4676G>T (p.Gly1559Val) in the first nucleotide‐binding domain exhibited non‐bullous congenital ichthyosiform erythroderma with lamellar scaling (PMID:22257947). Overall, ABCA12 variant spectrum includes missense substitutions predominantly in ATP‐binding cassettes, plus numerous truncating and splice‐site alleles.

Inheritance is strictly autosomal recessive, with affected individuals harboring homozygous or compound heterozygous ABCA12 variants. The c.4676G>T (p.Gly1559Val) missense change segregated with disease in five affected relatives in one family (PMID:22257947). Population‐specific or recurrent alleles have not been widely reported for lamellar ichthyosis, suggesting diverse private mutations across ethnicities.

Functional studies confirm that ABCA12 deficiency disrupts lipid transport in lamellar granules. Immunoelectron microscopy localized ABCA12 to lamellar granules in normal keratinocytes and demonstrated lipid secretion defects in patient cells. Corrective gene transfer of wild‐type ABCA12 restored lamellar granule lipid secretion in cultured keratinocytes from harlequin and lamellar ichthyosis patients (PMID:16007253). Mouse Abca12 knockout models recapitulate ichthyotic scaling and barrier defects, underscoring haploinsufficiency as the pathogenic mechanism (PMID:20672373).

No conflicting data disputing the ABCA12–lamellar ichthyosis link have been reported. The clinical phenotype is consistent across unrelated probands, segregation is complete in recessive families, and functional assays uniformly support loss of ABCA12 transporter activity. Additional unpublished deep‐intronic and large‐deletion variants have been identified but await functional confirmation.

In summary, biallelic ABCA12 pathogenic variants cause autosomal recessive lamellar ichthyosis via loss of lipid transporter function in keratinocyte lamellar granules. Molecular testing of ABCA12 informs definitive diagnosis, prognostic counseling, and prenatal screening for at-risk families.

References

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