ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

Abstract

Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATPbinding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

Prenatal Diagnosis of Harlequin Ichthyosis: Report of a Case

“…Unfortunately, as in our case, autosomal recessively inherited disorders are relatively common probably secondary to high percentage of related marriages in Turkey. To date, various ABCA12 mutations have been reported in HI patients [7]. Although some attemps were made to use DNAbased analysis for earlier (i.e., first trimester) prenatal testing [6], US and fetoscopic-or ultrasound-guided fetal skin biopsies are generally preferred for prenatal diagnosis.…”

Pharmacological Targeting of the Epidermal Barrier

“…Causative variations of the genes linked with abnormal lipid metabolism and transport and, thus consequently epidermal barrier dysfunction, can contribute to the development of clinical variants of the same disease with overlapping symptoms, since ALOX12B, ALOXE3, CYP4F22, NIPAL4, ABCA12 and LIPN mutations are frequently associated with the different clinical forms of autosomal recessive congenital ichthyosis [23,[25][26][27]32]. FALDH mutations result in Sjögren-Larsson syndrome [22].…”

ABC Proteins Protect the Human Body and Maintain Optimal Health

“…58) ABCA12 is expressed predominantly in an epidermal keratinocyte, and defective ABCA12 results in loss of the skin lipid barrier, leading to a devastating skin disorder, harlequin ichthyosis. 59) ABCA12 perhaps transports lipids, including glucosylceramide, into lamellar granules, which are secreted into the intercellular space forming the intercellular lipid layers, 60) but in many cases it is hard to determine which lipids are directly transported due to the hydrophobicity and low binding affinity. In the second half of this review, the mechanisms of the function and regulation of ABCA1, which have been most extensively studied among lipid-transporting ABC proteins, are summarized.…”