title: Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.
abstract: Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.
authors.affiliation: Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom. d.p.kelsell@qmul.ac.uk
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Norgett
authors.forename: Harriet
authors.initials: H
authors.lastname: Unsworth
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.forename: Thomas
authors.initials: T
authors.lastname: Cullup
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Dale
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tadini
authors.forename: Philip
authors.initials: P
authors.lastname: Fleckman
authors.forename: Karen G
authors.initials: KG
authors.lastname: Stephens
authors.forename: Virginia P
authors.initials: VP
authors.lastname: Sybert
authors.forename: Susan B
authors.initials: SB
authors.lastname: Mallory
authors.forename: Bernard V
authors.initials: BV
authors.lastname: North
authors.forename: David R
authors.initials: DR
authors.lastname: Witt
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Aileen E M
authors.initials: AE
authors.lastname: Taylor
authors.forename: Andrew
authors.initials: A
authors.lastname: Ilchyshyn
authors.forename: Cameron T
authors.initials: CT
authors.lastname: Kennedy
authors.forename: Helen
authors.initials: H
authors.lastname: Goodyear
authors.forename: Celia
authors.initials: C
authors.lastname: Moss
authors.forename: David
authors.initials: D
authors.lastname: Paige
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: Edel A
authors.initials: EA
authors.lastname: O'Toole
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics*; D007231:Infant, Newborn; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters