C-Terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload

Whatley, Sharon D., Ducamp, Sarah, Gouya, Laurent, Grandchamp, Bernard, Beaumont, Carole, Badminton, Michael Norman, Elder, George H., Holme, S. Alexander, Anstey, Alexander Vincent ORCID: https://orcid.org/0000-0002-6345-4144, Parker, Michelle, Corrigall, Anne V., Meissner, Peter N., Hift, Richard J., Marsden, Joanne T., Ma, Yun, Mieli-Vergani, Giorgina, Deybach, Jean-Charles and Puy, Hervé 2008. C-Terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. American Journal of Human Genetics 83 (3) , pp. 408-414. 10.1016/j.ajhg.2008.08.003

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Abstract

All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19–20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Sustainable Places Research Institute (PLACES)
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > R Medicine (General)
Publisher:	Elsevier
ISSN:	0002-9297
Last Modified:	06 May 2023 02:06
URI:	https://orca.cardiff.ac.uk/id/eprint/23722

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