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

Yu Fukuda,Pak Leng Cheong,Paul A Ney,Bing Yu,Robert C Ford,John D Schuetz,Evadnie Rampersaud,Sharon Frase,Vijay G Sankaran,Ronald J Trent,Peter Vogel,Cheryl Brighton,Mitchell J Weiss,Yao Wang,John Lynch,Vasileios Kargas,Peter J Bond

doi:10.1038/ncomms12353

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.

Highlights

Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates
In silico analyses[25] predicted that R276W and A681T are damaging variants (Supplementary Table 5). These computational approaches are not sensitive or specific[26], but our homology models for ABCB6, in both the inward-facing conformation (Supplementary Fig. 5, PDB ID 3ZDQ) and the outward-facing conformation (a model based on Sav1866 (PDB ID 2HYD)), suggest that the interaction between R276 and D397 would be disrupted with the latter exposed to the hydrophobic portion of the lipid bilayer
Discussion elevated porphyrins are a hallmark of multiple types of porphyria, the role of porphyrin transporters (TSPO, ABCG2, ABCB6 and FLVCR1) as modulators of disease severity has not been investigated

Summary

Introduction

Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. Homozygous disruption of the Abcb[6] gene in mice exacerbates porphyria phenotypes in the Fechm1Pas mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury 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( À ) blood type. Imposing Abcb[6] deletion on the Fechm1Pas mouse model exacerbates porphyria symptoms, as evidenced by increased red blood cell and hepatic porphyrin concentrations, and enhanced liver injury. These studies show that rare ABCB6 variant alleles modify the severity of porphyria symptoms in patients. Lan( À ) individuals are typically asymptomatic, the physiological function of plasma membrane ABCB6 is unknown

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Results

Conclusion