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

Item Type:Article
Title:X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation
Creators Name:Sankaran, V.G. and Ulirsch, J.C. and Tchaikovskii, V. and Ludwig, L.S. and Wakabayashi, A. and Kadirvel, S. and Lindsley, R.C. and Bejar, R. and Shi, J. and Lovitch, S.B. and Bishop, D.F. and Steensma, D.P.
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.
Keywords:5-Aminolevulinate Synthetase, Congenital Dyserythropoietic Anemia, Cultured Cells, Dominant Genes, Erythropoiesis, Exome, Hematologic Pregnancy Complications, Hemorrhage, Iron Overload, Macrocytic Anemia, Messenger RNA, Missense Mutation, Molecular Models, Molecular Sequence Data, Point Mutation, Pregnancy, Protein Binding, Protein Conformation, Puerperal Disorders, Pyridoxal Phosphate, Reticulocytes, X-Linked Genes, X-Linked Genetic Diseases, X Chromosome Inactivation
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:1665-1669
Date:1 April 2015
Additional Information:Erratum in: J Clin Invest 130(1): 552.
Official Publication:https://doi.org/10.1172/JCI78619
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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