C-Terminal Deletions in the ALAS2 Gene Lead to Gain of Function and Cause X-linked Dominant Protoporphyria without Anemia or Iron Overload Sharon D.

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C-Terminal Deletions in the ALAS2 Gene Lead to Gain of Function and Cause X-linked Dominant Protoporphyria without Anemia or Iron Overload Sharon D. Whatley, Sarah Ducamp, Laurent Gouya, Bernard Grandchamp, Carole Beaumont, Michael N. Badminton, George H. Elder, S. Alexander Holme, Alexander V. Anstey, Michelle Parker, Anne V. Corrigall, Peter N. Meissner, Richard J. Hift, Joanne T. Marsden, Yun Ma, Giorgina Mieli-Vergani, Jean-Charles Deybach, Hervé Puy The American Journal of Human Genetics Volume 83, Issue 3, Pages 408-414 (September 2008) DOI: 10.1016/j.ajhg.2008.08.003 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Treating Iron Deficiency Decreases Erythrocyte Protoporphyrin Concentrations Iron deficiency caused by bleeding from a gastric ulcer was treated with omeprazole and oral iron. The American Journal of Human Genetics 2008 83, 408-414DOI: (10.1016/j.ajhg.2008.08.003) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of Eight Families with FECH-Mutation-Negative Protoporphyria Green circles and squares represent patients with photosensitivity. Red circles and squares represent patients with photosensitivity and clinically overt liver disease. Protoporphyric liver disease was confirmed at autopsy or by needle biopsy in all these patients except patient I1 (family H), for whom a diagnosis has not been established. Patient II3 (family E) has been reported previously.23 Clinical information was not obtainable for patients C I, 3 and 4 or E I, 1 and 2. Black dots within circles or squares indicate individuals in whom either the delAGTG (families A–E, H) or delAT (families F and G) ALAS2 mutations were identified. Crosses within circles or squares indicate individuals in whom sequencing excluded the presence of an ALAS2 mutation. The absence of a black dot or cross indicates an individual from whom a DNA sample was not available for analysis. The LOD score for linkage between photosensitivity and the ALAS2 mutation was calculated for families A–E. The American Journal of Human Genetics 2008 83, 408-414DOI: (10.1016/j.ajhg.2008.08.003) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 C-Terminal Deletions in ALAS2 Cause X-Linked Dominant Protoporphyria (A) Sequence analysis of genomic DNA from male patients showing deletions in the ALAS2 gene. (B) Predicted effects of deletions on ALAS2 C-terminal sequences. (C–E) Prokaryotic expression of wild-type and mutant ALAS2 enzymes: Rates of formation of ALA (C) and porphyrin (D) by bacterial lysates; means and ranges for three experiments are shown. (E) Porphyrin fluorescence (UVA light) in bacterial pellets. The American Journal of Human Genetics 2008 83, 408-414DOI: (10.1016/j.ajhg.2008.08.003) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Comparison of C-terminal Sequences of ALAS enzymes (A) Alignment of ALAS C-terminal sequences. (B) Phylogenetic tree showing relationships between ALAS genes constructed with ClustalW. The American Journal of Human Genetics 2008 83, 408-414DOI: (10.1016/j.ajhg.2008.08.003) Copyright © 2008 The American Society of Human Genetics Terms and Conditions