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.

Figure 1

Typical clinical presentation of HI at birth

Figure 2

Localization of the HI gene to chromosome 2q35 by use of SNP-array mapping. A, Homozygous SNP profiles of chromosome 2 in six patients with HI. Black bars indicate homozygous SNP call data. Blue bars indicate the minimal common region of homozygous SNPs in patients 1–5, a genetic distance of ∼1.5 Mb. B, Ideogram of chromosome 2 showing the position of ABCA12 (red bar), located within the minimal common region of homozygous SNPs (blue) identified in panel A. C, The genetic interval of the homozygous SNP “blocks” in each patient with HI, with clear indication that the ABCA12 gene maps within the common homozygous region for five of the six patients.

Figure 3

Analysis of microsatellite markers flanking the ABCA12 gene. A, Segregation of microsatellite markers flanking ABCA12 at chromosome 2q35 in a family with HI. Only affected individual 6 is homozygous at this region of chromosome 2. Note that the majority of siblings with HI are deceased. B, Haplotype analysis of individuals with HI. Microsatellite markers map around the ABCA12 gene locus (215, 621, 772–215, 828, 657) at chromosome 2q35. Several patients are homozygous for the markers D2S325 (208, 096, 142–208, 096, 490), D2S128 (214, 917, 811–214, 918, 065), D2S1345 (214, 991, 103–214, 991, 425), and D2S126 (221, 842, 419–221, 842, 782). The genome positions (Mb) for ABCA12 and microsatellite markers on chromosome 2 are shown in parentheses.

Figure 4

Mutation analysis of the ABCA12 gene in patients with HI. A, Table summarizing mutation analysis. An asterisk (*) indicates a sequence change to a stop codon. B, i, Chromatogram showing homozygous GC deletion in exon 42 of patient 7. ii, Chromatogram showing homozygous T→C substitution in exon 44 in patient 955-01. iii, Chromatogram showing heterozygous A deletion in exon 33 of patient 44.