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Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP)
- Source :
- Human Molecular Genetics, 22(7), 1280-1288. Oxford University Press
- Publication Year :
- 2013
-
Abstract
- Frameshift mutations in the last coding exon of the 5-aminolevulinate synthase (ALAS) 2 gene were described to activate the enzyme causing increased levels of zinc- and metal-free protoporphyrin in patients with X-linked dominant protoporphyria (XLDPP). Only two such so-called gain-of-function mutations have been reported since the description of XLDPP in 2008. In this study of four newly identified XLDPP families, we identified two novel ALAS2 gene mutations, a nonsense p.Q548X and a frameshift c.1651-1677del26bp, along with a known mutation (delAGTG) found in two unrelated families. Of relevance, a de novo somatic and germinal mosaicism was present in a delAGTG family. Such a phenomenon may explain the high proportion of this mutation in XLDPP worldwide. Enhancements of over 3- and 14-fold in the catalytic rate and specificity constant of purified recombinant XLDPP variants in relation to those of wild-type ALAS2 confirmed the gain of function ascribed to these enzymes. The fact that both p.Q548X and c.1651-1677del26bp are located in close proximity and upstream from the two previously described mutations led us to propose the presence of a large gain-of-function domain within the C-terminus of ALAS2. To test this hypothesis, we generated four additional nonsense mutants (p.A539X, p.G544X, p.G576X and p.V583X) surrounding the human XLDPP mutations and defined an ALAS2 gain-of-function domain with a minimal size of 33 amino acids. The identification of this gain-of-function domain provides important information on the enzymatic activity of ALAS2, which was proposed to be constitutively inhibited, either directly or indirectly, through its own C-terminus.
- Subjects :
- Protoporphyria, Erythropoietic
DNA Mutational Analysis
Molecular Sequence Data
Mutant
Gene mutation
Biology
medicine.disease_cause
Frameshift mutation
Polar mutation
Young Adult
Exon
Genetics
medicine
Humans
Amino Acid Sequence
Frameshift Mutation
Molecular Biology
Gene
Genetic Association Studies
Genetics (clinical)
Mutation
Base Sequence
Mosaicism
Infant
Genetic Diseases, X-Linked
Exons
Sequence Analysis, DNA
General Medicine
ALAS2
Molecular biology
Pedigree
Protein Structure, Tertiary
Kinetics
Codon, Nonsense
Child, Preschool
Mutagenesis, Site-Directed
Female
5-Aminolevulinate Synthetase
Subjects
Details
- ISSN :
- 09646906
- Volume :
- 22
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....9244e3bd72f3b8e3237b9663aea8e4c3