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.
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.
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.
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.
Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis.
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.
We report the case of an infant with novel heterozygous mutations in ABCA12 who exhibited features and a clinical course more consistent with congenital ichthyosiform erythroderma than harlequin ichthyosis.
We reported two neonates with homozygous mutations in ABCA12 consistent with harlequin ichthyosis who survived to discharge home with intensive care and without use of systemic retinoids.