title: Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer.
abstract: Harlequin ichthyosis (HI) is a devastating skin disorder with an unknown underlying cause. Abnormal keratinocyte lamellar granules (LGs) are a hallmark of HI skin. ABCA12 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. ABCA3 is involved in lipid secretion via LGs from alveolar type II cells, and missense mutations in ABCA12 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 ABCA12 defects. We identify 5 distinct ABCA12 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 ABCA12. Immunoelectron microscopy revealed that ABCA12 localized to LGs in normal epidermal keratinocytes. We confirmed that ABCA12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA12. We concluded that ABCA12 works as an epidermal keratinocyte lipid transporter and that defective ABCA12 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.
authors: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. akiyama@med.hokudai.ac.jp
authors: Masashi
authors: M
authors: Akiyama
authors: Yoriko
authors: Y
authors: Sugiyama-Nakagiri
authors: Kaori
authors: K
authors: Sakai
authors: James R
authors: JR
authors: McMillan
authors: Maki
authors: M
authors: Goto
authors: Ken
authors: K
authors: Arita
authors: Yukiko
authors: Y
authors: Tsuji-Abe
authors: Nobuko
authors: N
authors: Tabata
authors: Kentaro
authors: K
authors: Matsuoka
authors: Rikako
authors: R
authors: Sasaki
authors: Daisuke
authors: D
authors: Sawamura
authors: Hiroshi
authors: H
authors: Shimizu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D001693:Biological Transport, Active; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D007231:Infant, Newborn; D015603:Keratinocytes / Q000378:metabolism / Q000648:ultrastructure; D008052:Lipid Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017386:Sequence Homology, Amino Acid
chemical_list: C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters