ABCB6 encodes a member of the ABC protein superfamily; ABC proteins are involved in the transport of various substrates across cell and organelle membranes. ABCB6 belongs to the Multi-Drug Resistance and Transporter associated Antigen Processing (MDR/TAP) family, one of 7 ABC families. The ABCB6 transmembrane protein is thought to function on the outer membrane of mitochondria and facilitate ATP-dependent uptake of porphyrin. Among its associated functions include heme biosynthesis, binding, and transport, as well as cellular iron ion homeostasis and brain development. Recent studies indicate ABCB6 localizes to the plasma membrane where it functions in drug transport and resistance and additionally forms the Langereis (Lan) blood antigen group present on red blood cells.
ABCB6 deficiency is the cause of multiple disorders including autosomal dominant (AD) pigmentary genodermatosis; AD isolated microphthlamia with coloboma; AD pseudohyperkalemia; as well as autosomal recessive deficiency resulting in an absence of Lan antigens on RBCs.
ABCB6 is located on the q arm of chromosome 2 and is 9,225 bases long, ranging from 219,209,766 to 219,218,990 base pairs pter. It contains 19 exons and translates into an 842aa long protein with a molecular weight of 93,886 Da. ABCB6 mRNA is expressed ubiquitously and is highly abundant in multiple tissues including brain, retina, liver, ovary, and testis. Protein expression is most abundant in nasal respiratory epithelium and peripheral blood mononuclear cells. 1 paralog and 1 alternatively spliced isoform have been identified. ABCB6 functions as a homodimer and exhibits half the number of domains found in other ABC proteins; among the domains include the nucleotide (ATP) binding and transmembrane domains.
Heterozygous and homozygous loss-of-function mutations in ABCB6 are the cause of multiple disorders: nonsense and missense heterozygous variants have been associated with pigmentary genodermatosis; missense variants are additionally associated with colobomatous microphthalmia and pseudohyperkalemia. Homozygous and compound heterozygous variants are associated with deficient Lan antigen formation on red blood cells, resulting in fetal hemolytic anemia and adverse response to blood transfusion.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient was diagnosed with autosomal dominant Microphthalmia, Isolated, with Coloboma 7 (MCOPCB7). Two heterozygous missense mutations in ABCB6 (c.4G>A, p.Val91Met; c.904C>G, p.Leu302Val) was identified as the probable cause. A third heterozygous missense transition in CHD7 (c.5689G>A; p.Glu1897Lys), associated with CHARGE syndrome was also identified. The patient’s father harbored similar symptoms and identical heterozygous mutations.
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