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.
Kelsell
David P
DP
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
Norgett
Elizabeth E
EE
Unsworth
Harriet
H
Teh
Muy-Teck
MT
Cullup
Thomas
T
Mein
Charles A
CA
Dopping-Hepenstal
Patricia J
PJ
Dale
Beverly A
BA
Tadini
Gianluca
G
Fleckman
Philip
P
Stephens
Karen G
KG
Sybert
Virginia P
VP
Mallory
Susan B
SB
North
Bernard V
BV
Witt
David R
DR
Sprecher
Eli
E
Taylor
Aileen E M
AE
Ilchyshyn
Andrew
A
Kennedy
Cameron T
CT
Goodyear
Helen
H
Moss
Celia
C
Paige
David
D
Harper
John I
JI
Young
Bryan D
BD
Leigh
Irene M
IM
Eady
Robin A J
RA
O'Toole
Edel A
EA
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
C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters