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