Journal Article

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

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

2016

Overview

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. Accumulation of intermediates of haem biosynthesis, porphyrins, is harmful and usually inherited, but it is unclear how the same mutation may make some individuals more ill than others. Here, the authors show that a porphyrin transporter ABCB6 is a modulator of porphyria, and that patients with functionally defective ABCB6 show more severe symptoms.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 38/109 / 38/23 / 631/208/2490 / 692/699/1541 / ABC transporters / Alleles / Animals / Antigens / ATP-Binding Cassette Transporters - genetics / ATP-Binding Cassette Transporters - metabolism / Biological Transport - genetics / Biology / Biosynthesis / Blood / Cell Membrane - metabolism / Cohort Studies / Disease Models, Animal / Enzymes / Female / Genes / Genomics / Hematology / Heme - biosynthesis / Heme - metabolism / Hospitals / Humanities and Social Sciences / Humans / Isoantigens - blood / Isoantigens - genetics / Isoantigens - metabolism / Liver / Male / Metabolism / Mice / Mice, Inbred BALB C / Mice, Knockout / multidisciplinary / Mutation / Patients / Plasma / Porphyrias - genetics / Porphyrias - metabolism / Porphyrias - urine / Porphyrins - metabolism / Porphyrins - urine / Science / Science (multidisciplinary) / Sequence Homology, Amino Acid / Severity of Illness Index / Whole Exome Sequencing