title: Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.
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.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Hildick-Smith
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cooney
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Thon
authors.forename: Non
authors.initials: N
authors.lastname: Miyata
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lieber
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: H Orhan
authors.initials: HO
authors.lastname: Akman
authors.forename: Yvette Y
authors.initials: YY
authors.lastname: Yien
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Huston
authors.forename: Diana S
authors.initials: DS
authors.lastname: Branco
authors.forename: Dhvanit I
authors.initials: DI
authors.lastname: Shah
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Carla M
authors.initials: CM
authors.lastname: Koehler
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.forename: Andreas
authors.initials: A
authors.lastname: Merkenschlager
authors.forename: Skadi
authors.initials: S
authors.lastname: Beblo
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.forename: M Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
mesh_terms: D000293:Adolescent; D000748:Anemia, Macrocytic / Q000235:genetics*; D000818:Animals; D002648:Child; D004920:Erythropoiesis / Q000235:genetics; D059472:Exome; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D015027:Zebrafish / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C488377:SFXN4 protein, human