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Nat Commun. 2016 Aug 10;7:12353. doi: 10.1038/ncomms12353.

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

Author information

1
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
2
Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
3
Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
4
Department of Tissue Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
5
Department of Structural Biology, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
6
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
7
Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
8
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
9
New York Blood Center, New York, New York 10065, USA.
10
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
11
Bioinformatics Institute, 30 Biopolis Street, Singapore 138671, Singapore.
12
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.

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.

PMID:
27507172
PMCID:
PMC4987512
DOI:
10.1038/ncomms12353
[Indexed for MEDLINE]
Free PMC Article

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