title: 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 Fech(m1Pas) 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.
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Yu
authors: Y
authors: Fukuda
authors: Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Pak Leng
authors: 0000-0002-0095-4459
authors: PL
authors: Cheong
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: John
authors: J
authors: Lynch
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Cheryl
authors: C
authors: Brighton
authors: Department of Tissue Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Sharon
authors: S
authors: Frase
authors: Department of Structural Biology, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Vasileios
authors: V
authors: Kargas
authors: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Evadnie
authors: E
authors: Rampersaud
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Yao
authors: Y
authors: Wang
authors: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Vijay G
authors: VG
authors: Sankaran
authors: Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Bing
authors: 0000-0001-6013-5220
authors: B
authors: Yu
authors: New York Blood Center, New York, New York 10065, USA.
authors: Paul A
authors: PA
authors: Ney
authors: Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Mitchell J
authors: MJ
authors: Weiss
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Peter
authors: P
authors: Vogel
authors: Bioinformatics Institute, 30 Biopolis Street, Singapore 138671, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
authors: Peter J
authors: PJ
authors: Bond
authors: Department of Structural Biology, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Robert C
authors: RC
authors: Ford
authors: Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Ronald J
authors: RJ
authors: Trent
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: John D
authors: JD
authors: Schuetz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006418:Heme / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007519:Isoantigens / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D011164:Porphyrias / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D011166:Porphyrins / Q000378:metabolism* / Q000652:urine; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index; D000073359:Exome Sequencing
chemical_list: C107991:ABCB6 protein, human; D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; D007519:Isoantigens; C083301:LAN antigen; D011166:Porphyrins; D006418:Heme