C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload by Whatley Sharon D, Ducamp Sarah, Gouya Laurent, Grandchamp Bernard, Beaumont Carole, Badminton Michael N, Elder George H, Holme S Alexander, Anstey Alexander V, Parker Michelle, Corrigall Anne V, Meissner Peter N, Hift Richard J, Marsden Joanne T, Ma Yun, Mieli-Vergani Giorgina, Deybach Jean-Charles, Puy Hervé in American journal of human genetics (2008).

[PMID: 18760763] PubMed


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.

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