X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      Mutation, Missense* ; Point Mutation*; 5-Aminolevulinate Synthetase/*genetics ; Anemia, Dyserythropoietic, Congenital/*genetics ; Anemia, Macrocytic/*genetics ; Erythropoiesis/*genetics ; Genetic Diseases, X-Linked/*genetics; 5-Aminolevulinate Synthetase/metabolism ; Adult ; Cells, Cultured ; Exome/genetics ; Female ; Genes, Dominant ; Genes, X-Linked ; Genetic Diseases, X-Linked/blood ; Hemorrhage/etiology ; Humans ; Iron Overload/etiology ; Male ; Models, Molecular ; Molecular Sequence Data ; Pregnancy ; Pregnancy Complications, Hematologic/genetics ; Protein Binding ; Protein Conformation ; Puerperal Disorders/etiology ; Pyridoxal Phosphate/metabolism ; RNA, Messenger/genetics ; Reticulocytes/metabolism ; X Chromosome Inactivation
    • Abstract:
      Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5'-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5'-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease.
    • Comments:
      Erratum in: J Clin Invest. 2020 Jan 2;130(1):552. (PMID: 31895053)
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    • Grant Information:
      R01 DK103794 United States DK NIDDK NIH HHS; R21 HL120791 United States HL NHLBI NIH HHS; T32 CA009172 United States CA NCI NIH HHS
    • Molecular Sequence:
      dbGaP PHS000474.V2.P1
    • Accession Number:
      0 (RNA, Messenger)
      5V5IOJ8338 (Pyridoxal Phosphate)
      EC 2.3.1.37 (5-Aminolevulinate Synthetase)
      EC 2.3.1.37 (ALAS2 protein, human)
    • Publication Date:
      Date Created: 20150224 Date Completed: 20150702 Latest Revision: 20181113
    • Publication Date:
      20231215
    • Accession Number:
      PMC4396476
    • Accession Number:
      10.1172/JCI78619
    • Accession Number:
      25705881