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

Yu Fukuda, Pak Leng Cheong, John Lynch, Cheryl Brighton, Sharon Frase, Vasileios Kargas, Evadnie Rampersaud, Yao Wang, Vijay G. Sankaran, Bing Yu, Paul A. Ney, Mitchell J. Weiss, Peter Vogel, Peter J. Bond, Robert C. Ford, Ronald J. Trent and John D. Schuetz ()
Additional contact information
Yu Fukuda: St Jude Children’s Research Hospital
Pak Leng Cheong: Royal Prince Alfred Hospital
John Lynch: St Jude Children’s Research Hospital
Cheryl Brighton: St Jude Children’s Research Hospital
Sharon Frase: St Jude Children’s Research Hospital
Vasileios Kargas: Faculty of Life Sciences, University of Manchester
Evadnie Rampersaud: St Jude Children’s Research Hospital
Yao Wang: St Jude Children’s Research Hospital
Vijay G. Sankaran: Boston Children’s Hospital
Bing Yu: Royal Prince Alfred Hospital
Paul A. Ney: New York Blood Center
Mitchell J. Weiss: St Jude Children’s Research Hospital
Peter Vogel: St Jude Children’s Research Hospital
Peter J. Bond: Bioinformatics Institute
Robert C. Ford: Faculty of Life Sciences, University of Manchester
Ronald J. Trent: Royal Prince Alfred Hospital
John D. Schuetz: St Jude Children’s Research Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12353

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