The present patient demonstrates that rapid diagnosis of HI by ABCA12 expression analysis and mutation detection, and early commencement of systemic retinoid therapy are crucial to significantly improving an HI patient's prognosis.
We confirmed that ABCA12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA12.
This article reviews current opinions on the patho-mechanisms of ABCA12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies.
Until the identification of ABCA12 as the causative gene, prenatal diagnosis (PND) for HI had been performed by electronmicroscopic observation of fetal skin biopsy samples.
Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown.
In fact, loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in the HI phenotype and ABCA12 is a known keratinocyte lipid transporter associated with lipid transport in lamellar granules.
Recently, mutations in two ABC-transporter genes, ABCC6 and ABCA12, have been demonstrated to underlie phenotypically different diseases affecting the skin (pseudoxanthoma elasticum and harlequin ichthyosis, respectively), attesting to the spectrum of ABC gene mutations in human diseases.
Autosomal recessive congenital ichthyosis (ARCI4B [OMIM #242500]), also known as harlequin ichthyosis, presents at birth with extreme hyperkeratosis and thick-fissured plaques, leading to tightness of the skin around the eyes, mouth, ears, chest, abdomen, and extremities.
One of these components, ABCA12, has recently been shown to be 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 the HI phenotype.
ABCA12 mutations are known to underlie the three major types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma.