Macrocytic Anemia and Mitochondriopathy Resulting from a Defect in Sideroflexin 4

Author(s):Show less -

Hildick-Smith, Gordon J. ^{[1, 2]} ; Cooney, Jeffrey D. ^{[1, 2]} ; Garone, Caterina ^[3] ; Kremer, Laura S. ^{[4, 5]} ; Haack, Tobias B. ^{[4, 5]} ; Thon, Jonathan N. ^{[1, 2]} ; Miyata, Non ^[6] ; Lieber, Daniel S. ^{[7, 8, 9, 10]} ; Calvo, Sarah E. ^{[7, 8, 9, 10]} ; Akman, H. Orhan ^[3] ; Yien, Yvette Y. ^{[1, 2]} ; Huston, Nicholas C. ^{[1, 2]} ; Branco, Diana S. ^{[1, 2]} ; Shah, Dhvanit I. ^{[1, 2]} ; Freedman, Matthew L. ^{[1, 11]} ; Koehler, Carla M. ^[6] ; Italiano, Jr., Joseph E. ^{[1, 2]} ; Merkenschlager, Andreas ^[12] ; Beblo, Skadi ^[13] ; Strom, Tim M. ^{[4, 5]} ; Meitinger, Thomas ^{[4, 5]} ; Freisinger, Peter ^[14] ; Donati, M. Alice ^[15] ; Prokisch, Holger ^{[4, 5]} ; Mootha, Vamsi K. ^{[7, 8, 9, 10]} ; DiMauro, Salvatore ^[3] ; Paw, Barry H. ^{[1, 2, 16, 17]}

Affiliation:Show less -

^[1] Harvard Univ, Sch Med, Boston, MA 02115 - USA

^[2] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 - USA

^[3] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 - USA

^[4] Tech Univ Munich, Inst Human Genet, D-80333 Munich - Germany

^[5] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg - Germany

^[6] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 - USA

^[7] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 - USA

^[8] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 - USA

^[9] Harvard Univ, Sch Med, Boston, MA 02114 - USA

^[10] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 - USA

^[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 - USA

^[12] Univ Leipzig, Univ Hosp Children & Adolescents, Dept Neuropediat, D-04103 Leipzig - Germany

^[13] Univ Leipzig, Univ Hosp Children & Adolescents, Dept Inborn Metab Dis, D-04103 Leipzig - Germany

^[14] Kinderklin Klinikum Reutlingen, Dept Pediat, D-72764 Reutlingen - Germany

^[15] Meyer Children Hosp, Unit Metab & Muscular Dis, I-50132 Florence - Italy

^[16] Boston Childrens Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02115 - USA

^[17] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 - USA

• Document type: Journal article
• Source: American Journal of Human Genetics; v. 93, n. 5, p. 906-914, NOV 7 2013.
• Web of Science Citations: 15

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. (AU)