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.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…We propose that ''ARCI'' should be used to refer to harlequin ichthyosis (HI) and disorders of the LI/CIE phenotypic spectrum (Table V) exclusively. HI (Fig 2, A) was included, because functional null mutations in the ABCA12 gene cause the disease, 15,16 whereas missense mutations in the same gene may result in a milder phenotype that shows collodion membrane at birth and develops into LI 17,18 or CIE, 19,20 often with palmoplantar keratoderma (PPK). Those infants with HI who survive the perinatal period go on to express a severe and very scaling erythroderma 21 ( Fig 2, B and C ).…”

A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments

“…The ABCA3 WT /FLAG was used as a template to generate mutant constructs using the primers in supplementary Table I and a one-step PCR amplifi cation and subcloning approach using the QuikChange II XL Site-Directed Mutagenesis Kit according to the manufacturer's instructions (Stratagene, La Jolla, CA). To generate all six consecutive alanine mutations using this kit, two rounds of PCR amplifi cation ABCA7, ABCA9, ABCA10, and ABCA12 , suggest a distinct role for each of these transporters in lipid homeostasis functioning in various subcellular compartments as well (8)(9)(10)(11). To date, 12 members of the human and 16 members of the rodent ABCA transporter families have been identifi ed ( 12 ).…”

Harlequin Baby

“…It is the most severe form of congenital ichthyosis, with autosomal recessive inheritance. The underlying genetic abnormality has been identified as a mutation in the lipid-transporter gene ABeAl2 on chromosome 2 [2,3]. Incidence is 1 in 1 million births and more than 100 cases have been reported so far [4].…”