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.
| Predicate | Object |
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| rdf:type | |
| rdfs:comment |
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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| skos:exactMatch | |
| uniprot:name |
Am. J. Hum. Genet.
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| uniprot:author |
Anstey A.V.,
Badminton M.N.,
Beaumont C.,
Corrigall A.V.,
Deybach J.C.,
Ducamp S.,
Elder G.H.,
Gouya L.,
Grandchamp B.,
Hift R.J.,
Holme S.A.,
Ma Y.,
Marsden J.T.,
Meissner P.N.,
Mieli-Vergani G.,
Parker M.,
Puy H.,
Whatley S.D.
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| uniprot:date |
2008
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| uniprot:pages |
408-414
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| uniprot:title |
C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.
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| uniprot:volume |
83
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| dc-term:identifier |
doi:10.1016/j.ajhg.2008.08.003
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