Jerome Clayton

Publications (2)17.53 Total impact

• Article: Molecular and Functional Analysis of the C-Terminal Region of Human Erythroid Specific 5-Aminolevulinic Synthase Associated with X-Linked Dominant Protoporphyria (XLDPP).

  Sarah Ducamp, Xiaoye Schneider-Yin, Felix de Rooij, Jerome Clayton, Erica J Fratz, Alice Rudd, George Ostapowicz, George Varigos, Thibaud Lefebvre, Jean-Charles Deybach, Laurent Gouya, Paul Wilson, Gloria C Ferreira, Elisabeth I Minder, Hervé Puy
  [show abstract] [hide abstract]
  ABSTRACT: Frameshift mutations in the last coding exon of the 5-aminolevulinate synthase (ALAS) 2 gene were described to activate the enzyme and 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.1651-1677del26 bp, 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 world-wide. 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.1651-1677del26 bp 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.
  Human Molecular Genetics 12/2012; · 7.64 Impact Factor
• Article: ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.

  Jordi To-Figueras, Sarah Ducamp, Jerome Clayton, Celia Badenas, Constance Delaby, Cecile Ged, Said Lyoumi, Laurent Gouya, Hubert de Verneuil, Carole Beaumont, Gloria C Ferreira, Jean-Charles Deybach, Carmen Herrero, Herve Puy
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.
  Blood 06/2011; 118(6):1443-51. · 9.90 Impact Factor