The ABCA12 gene encodes for the ATP-binding cassette sub-family A member 12 transporter protein. Transporter proteins carry out the active transportation of various molecules across extra- and intracellular membranes. The ABCA12 protein plays a major role in lipid transport in cells that make up the epidermis. This lipid transport appears to be important for normal development of the skin. Studies on animal models have suggested that the protein plays a critical role in the formation of the skin's permeability barrier via an effect on the generation of a highly specialized class of ceramide esters.
Mutations in ABCA12 have been associated with disruption of the lamellar permeability barrier and skin ichthyoses of variable severity. These include conditions like Ichthyosis, Congenital, Autosomal Recessive 4A and Harlequin Ichthyosis.
The ABCA12 gene is located on the long arm of chromosome 2, where it spans a length of 206 Kb. The gene consists of 53 exons, that together code for a 2595 amino acid protein with a molecular mass of 293 kDa. The fully functional protein contains two transmembrane domains, each with about six membrane-spanning segments, and two ATP-binding domains or nucleotide-binding folds (NBF), which are located in the cytoplasm.
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Wakil et al., (2016) described two unrelated Saudi patients with Autosomal Recessive Congenital Ichthyosis. Both patients were born to consanguineous parents. The authors found one novel mutation (p.Phe2300Leu) and one reported mutation (p.Ser1157Leu) in the ABCA12 gene in the two families. Combined approach of homozygosity mapping and direct sequencing analysis was helpful in confirming the diagnosis of these patients.
Bastaki et al. (2017) studied Emirati congenital ichthyosis patients. They described a 5-month-old male suffering from thick, shiny, scaly skin, single bilateral palmar creases, bilateral sole swelling, and small toes. He had a similarly affected older brother. His parents were healthy and not related. WES uncovered 3 heterozygous mutations in the ABCA12 gene of both brothers: two known missense mutations (c.2785C>T, pArg929Cys; c.6852G>C, p.Glu2284Asp) and a novel frameshift (c.335_336delC, p.Ser112tyrfs*25). The frameshift was predicted to result in nonsense mediated decay and both missense variants were predicted to be functionally damaging. The father was found to carry both heterozygous missense mutations while the mother had the heterozygous frameshift variant. The authors also described a 1.5-year-old male child born to healthy consanguineous parents. He suffered from generalized scaling of the skin, erythroderma, eclabium and severe ectropion. He was diagnosed with Harlequin Ichthyosis and an ABCA12 screening revealed a homozygous c.2487dupT (p.Arg830Glufs*16) mutation. The duplication was predicted to result in nonsense mediated decay and both parents were found to be heterozygous carriers.
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