The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6

Abstract

Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. A long-standing open question is why the same causal porphyria mutations exhibit widely variable penetrance and expressivity in different individuals. Here we show that severely affected porphyria patients harbour variant alleles in the ABCB6 gene, also known as Lan, which encodes an ATP-binding cassette (ABC) transporter. Plasma membrane ABCB6 exports a variety of disease-related porphyrins. Functional studies show that most of these ABCB6 variants are expressed poorly and/or have impaired function. Accordingly, homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes in the Fechm1Pas mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury. Collectively, these studies support ABCB6 role as a genetic modifier of porphyria and suggest that porphyrin-inducing drugs may produce excessive toxicities in individuals with the rare Lan(−) blood type.

ABCB6, an ABC Transporter Impacting Drug Response and Disease

“…Given, TMD0 in other ABC transporters has been shown to mediate protein-protein interactions, we speculate that TMD0 mediates interactions with chaperones or other effector proteins that aid in assembling tertiary structural elements or guiding ABCB6 to its final destination. This is exemplified in the Lan mutant R192Q (in TMD0) where near normal ATP and heme binding is observed, but surface expression is severely diminished (16) or absent (17). This suggests TMD0 has an important, but currently undetermined role that is independent of substrate binding and translocation.…”

“…Indeed, a long-standing clinical mystery has been why some porphyria patients become more ill than others, even when harboring the same heme biosynthetic defect. Recently, using a well-characterized cohort of porphyria patients coupled with an unbiased genomic analysis, it was determined by whole exome sequencing and pathway analysis that ABCB6 was a genetic modifier of porphyria (16), and corresponding rare variants are listed in Table 2. Plasma membrane ABCB6 was shown to bea high affinity exporter of cytotoxic porphyrins.…”

“…Plasma membrane ABCB6 was shown to bea high affinity exporter of cytotoxic porphyrins. Furthermore, it was established that the ABCB6 variants behaved like dominant negatives (16), and are likely degraded by the proteasome (Figure 4). From these findings a new porphyria-prone animal model was developed.…”

“… * This table was curated from the following references: (16, 17, 48, 49, 54–59) ** Allele Frequencies MAF% were obtained from NHLBI GO Exome Sequencing Project (ESP) Exome VariantVariant Server (http://evs.gs.washington.edu/EVS/) accessed on August 14, 2017. …”

“…ABCB6 was originally identified in 1997 while screening for novel ABC transporter genes associated with drug resistance in the liver (5). Since then, the biological impact of ABCB6 has expanded to include: resistance to toxic metals (6), protection against oxidative (7) and phenylhydrazine stress (8), potential roles in promoting tumor growth and proliferation (5, 9, 10), acquired chemotherapeutic resistance (11–15), facilitation of de novo porphyrin biosynthesis (4, 16), and encoding the blood group system, Langereis ( Lan ) (17). It is unknown how many of these phenotypes are directly related to the function of ABCB6, or if these observations or related to downstream perturbations.…”