1. Macrocytic Anemia and Mitochondriopathy Resulting from a Defect in Sideroflexin 4
- Author
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Diana S. Branco, Vamsi K. Mootha, Tim M. Strom, Salvatore DiMauro, Barry H. Paw, H. Orhan Akman, Jonathan N. Thon, Sarah E. Calvo, Laura S. Kremer, Jeffrey D. Cooney, Skadi Beblo, Joseph E. Italiano, Carla M. Koehler, Gordon J. Hildick-Smith, Holger Prokisch, Andreas Merkenschlager, Yvette Y. Yien, Peter Freisinger, Tobias B. Haack, Nicholas C. Huston, Daniel S. Lieber, Caterina Garone, Dhvanit I. Shah, Matthew L. Freedman, Thomas Meitinger, Non Miyata, M. Alice Donati, Hildick-Smith G.J., Cooney J.D., Garone C., Kremer L.S., Haack T.B., Thon J.N., Miyata N., Lieber D.S., Calvo S.E., Akman H.O., Yien Y.Y., Huston N.C., Branco D.S., Shah D.I., Freedman M.L., Koehler C.M., Italiano Jr. J.E., Merkenschlager A., Beblo S., Strom T.M., Meitinger T., Freisinger P., Donati M.A., Prokisch H., Mootha V.K., DiMauro S., and Paw B.H.
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Mitochondrial Diseases ,Macrocytic ,medicine.disease_cause ,Medical and Health Sciences ,0302 clinical medicine ,Mitochondrial Disease ,Erythropoiesi ,Genetics(clinical) ,Erythropoiesis ,Exome ,Anemia, Macrocytic ,Child ,Inner mitochondrial membrane ,Membrane Protein ,Zebrafish ,Genetics (clinical) ,Exome sequencing ,Pediatric ,Genetics & Heredity ,0303 health sciences ,Mutation ,Anemia ,Hematology ,Biological Sciences ,3. Good health ,Gene Knockdown Techniques ,Female ,Human ,Adolescent ,Mitochondrial disease ,Biology ,Mitochondrial Proteins ,03 medical and health sciences ,Report ,Genetics ,medicine ,Mitochondrial Protein ,Animals ,Humans ,030304 developmental biology ,Animal ,Membrane Proteins ,medicine.disease ,biology.organism_classification ,Molecular biology ,Gene Knockdown Technique ,Immunology ,Macrocytic anemia ,030217 neurology & neurosurgery - Abstract
We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respiratory defect observed in both individuals and the macrocytic anemia with megaloblastic features of the more severe case. In vitro and in vivo complementation studies with fibroblasts from the affected individuals and zebrafish demonstrated the requirement of SFXN4 for mitochondrial respiratory homeostasis and erythropoiesis. Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia. © 2013 by The American Society of Human Genetics. All rights reserved.
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