title: A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia.
abstract: The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder.
authors.affiliation: Department of Pathology and.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lichtenstein
authors.affiliation: Department of Pathology and.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Crispin
authors.affiliation: Department of Pathology and.
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Sendamarai
authors.affiliation: Department of Pathology and.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Cristovao M
authors.initials: CM
authors.lastname: Sousa
authors.affiliation: Division of Hematology, Brigham and Women's Hospital and Boston Children's Hospital, Boston, MA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Kafina
authors.affiliation: Department of Pathology and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Schmidt
authors.affiliation: Department for Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.affiliation: Division of Haematology, King's College, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Porter
authors.affiliation: Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: May
authors.affiliation: Division of Hematology-Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Patnaik
authors.affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Heeney
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Radiation Oncology, New York University Langone Cancer Center, New York, NY; and.
authors.forename: Alec
authors.initials: A
authors.lastname: Kimmelman
authors.affiliation: University of Oklahoma College of Medicine, Oklahoma City, OK.
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Bottomley
authors.affiliation: Division of Hematology, Brigham and Women's Hospital and Boston Children's Hospital, Boston, MA.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
authors.affiliation: Department of Pathology and.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Department of Pathology and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000756:Anemia, Sideroblastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D017384:Sequence Deletion
chemical_list: C518653:NDUFB11 protein, human; D042967:Electron Transport Complex I