title: C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.
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.
authors.affiliation: Department of Medical Biochemistry and Immunology, University Hospital of Wales and, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Whatley
authors.forename: Sarah
authors.initials: S
authors.lastname: Ducamp
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Michael N
authors.initials: MN
authors.lastname: Badminton
authors.forename: George H
authors.initials: GH
authors.lastname: Elder
authors.forename: S Alexander
authors.initials: SA
authors.lastname: Holme
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Anstey
authors.forename: Michelle
authors.initials: M
authors.lastname: Parker
authors.forename: Anne V
authors.initials: AV
authors.lastname: Corrigall
authors.forename: Peter N
authors.initials: PN
authors.lastname: Meissner
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hift
authors.forename: Joanne T
authors.initials: JT
authors.lastname: Marsden
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy