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Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.

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.

Pubmed ID: 15756637


  • Kelsell DP
  • Norgett EE
  • Unsworth H
  • Teh MT
  • Cullup T
  • Mein CA
  • Dopping-Hepenstal PJ
  • Dale BA
  • Tadini G
  • Fleckman P
  • Stephens KG
  • Sybert VP
  • Mallory SB
  • North BV
  • Witt DR
  • Sprecher E
  • Taylor AE
  • Ilchyshyn A
  • Kennedy CT
  • Goodyear H
  • Moss C
  • Paige D
  • Harper JI
  • Young BD
  • Leigh IM
  • Eady RA
  • O'Toole EA


American journal of human genetics

Publication Data

May 4, 2005

Associated Grants

  • Agency: NIAMS NIH HHS, Id: 2P01 AR 21557

Mesh Terms

  • ATP-Binding Cassette Transporters
  • Base Sequence
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2
  • Humans
  • Ichthyosis, Lamellar
  • Infant, Newborn
  • Microsatellite Repeats
  • Molecular Sequence Data
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide