Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer.

[harlequin ichthyosis]

Harlequin ichthyosis (HI ) is a devastating skin disorder with an unknown underlying cause . Abnormal keratinocyte lamellar granules (LGs ) are a hallmark of HI skin . ABCA 12 is a member of the ATP-binding cassette transporter family , and members of the ABCA subfamily are known to have closely related functions as lipid transporters . ABCA 3 is involved in lipid secretion via LGs from alveolar type II cells , and missense mutations in ABCA 12 have been reported to cause lamellar ichthyosis type 2 , a milder form of ichthyosis . Therefore , we hypothesized that HI might be caused by mutations that lead to serious ABCA 12 defects . We identify 5 distinct ABCA 12 mutations , either in a compound heterozygous or homozygous state , in patients from 4 HI families . All the mutations resulted in truncation or deletion of highly conserved regions of ABCA 12 . Immunoelectron microscopy revealed that ABCA 12 localized to LGs in normal epidermal keratinocytes . We confirmed that ABCA 12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA 12 . We concluded that ABCA 12 works as an epidermal keratinocyte lipid transporter and that defective ABCA 12 results in a loss of the skin lipid barrier , leading to HI . Our findings not only allow DNA-based early prenatal diagnosis but also suggest the possibility of gene therapy for HI .