Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis

David P. Kelsell, Elizabeth E. Norgett, Harriet Unsworth, Muy Teck Teh, Thomas Cullup, Charles A. Mein, Patricia J. Dopping-Hepenstal, Beverly A. Dale, Gianluca Tadini, Philip Fleckman, Karen G. Stephens, Virginia P. Sybert, Susan B. Mallory, Bernard V. North, David R. Witt, Eli Sprecher, Aileen E M Taylor, Andrew Ilchyshyn, Cameron T. Kennedy, Helen GoodyearCelia Moss, David Paige, John I. Harper, Bryan D. Young, Irene M. Leigh, Robin A J Eady, Edel A. O'Toole

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)794-803
Number of pages10
JournalAmerican Journal of Human Genetics
Volume76
Issue number5
DOIs
Publication statusPublished - May 2005

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Lamellar Ichthyosis
Skin Diseases
Mutation
Ichthyosis
Lipids
Phosphoprotein Phosphatases
Extracellular Space
Prenatal Diagnosis
Epidermis
Single Nucleotide Polymorphism
Early Diagnosis
Carrier Proteins
Technology
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Kelsell, D. P., Norgett, E. E., Unsworth, H., Teh, M. T., Cullup, T., Mein, C. A., ... O'Toole, E. A. (2005). Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. American Journal of Human Genetics, 76(5), 794-803. https://doi.org/10.1086/429844

Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. / 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, Vol. 76, No. 5, 05.2005, p. 794-803.

Research output: Contribution to journalArticle

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, AEM, Ilchyshyn, A, Kennedy, CT, Goodyear, H, Moss, C, Paige, D, Harper, JI, Young, BD, Leigh, IM, Eady, RAJ & O'Toole, EA 2005, 'Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis', American Journal of Human Genetics, vol. 76, no. 5, pp. 794-803. https://doi.org/10.1086/429844
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. / Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. In: American Journal of Human Genetics. 2005 ; Vol. 76, No. 5. pp. 794-803.
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