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Three kinships with alas2 p520l (c. 1559 c -> t) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload

Academic Article
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Overview

authors

  • Lee, Pauline
  • Barton, J. C.
  • Rao, S. V.
  • Acton, R. T.
  • Adler, B. K.
  • Beutler, Ernest

publication date

  • March 2006

journal

  • Blood Cells Molecules and Diseases  Journal

abstract

  • Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if "mild" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.

subject areas

  • 5-Aminolevulinate Synthetase
  • Adult
  • Aged
  • Anemia, Sideroblastic
  • Continental Population Groups
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Genotype
  • Histocompatibility Antigens Class I
  • Humans
  • Iron Overload
  • Male
  • Membrane Proteins
  • Pedigree
  • Point Mutation
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Research

keywords

  • X-linked sideroblastic anemia
  • hemochromatosis
  • iron overload
  • modifier
  • mutation
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Identity

International Standard Serial Number (ISSN)

  • 1079-9796

Digital Object Identifier (DOI)

  • 10.1016/j.bcmd.2005.12.004

PubMed ID

  • 16446107
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Additional Document Info

start page

  • 292

end page

  • 297

volume

  • 36

issue

  • 2

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