Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis by Kelsell David P, Norgett Elizabeth E, Unsworth Harriet, Teh Muy-Teck, Cullup Thomas, Mein Charles A, Dopping-Hepenstal Patricia J, Dale Beverly A, Tadini Gianluca, Fleckman Philip, Stephens Karen G, Sybert Virginia P, Mallory Susan B, North Bernard V, Witt David R, Sprecher Eli, Taylor Aileen E M, Ilchyshyn Andrew, Kennedy Cameron T, Goodyear Helen, Moss Celia, Paige David, Harper John I, Young Bryan D, Leigh Irene M, Eady Robin A J, O'Toole Edel A in American journal of human genetics (2005). PubMed

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.

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