Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.

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

Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4

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. \ua9 2013 by The American Society of Human Genetics. All rights reserved

Genomic organization and sequence dynamics of the AvrPiz-t locus in Magnaporthe oryzae *

Plants utilize multiple layers of defense mechanisms to fight against the invasion of diverse pathogens. The R gene mediates resistance, in most cases, dependent on the co-existence of its cognate pathogen-derived avirulence (Avr) gene. The rice blast R gene Piz-t corresponds in gene-for-gene fashion to the Magnaporthe oryzae Avr gene AvrPiz-t. In this study, we determined and compared the genomic sequences surrounding the AvrPiz-t gene in both avirulent and virulent isolates, designating as AvrPiz-t-ZB15 and avrPiz-t-70-15 regions, respectively. The sequence of the AvrPiz-t-ZB15 region is 120 966 bp whereas avrPiz-t-70-15 is 146 292 bp in length. The extreme sequence similarity and good synteny in gene order and content along with the absence of two predicted genes in the avrPiz-t-70-15 region were observed in the predicted protein-coding regions in the AvrPiz-t locus. Nevertheless, frequent presence/absence and highly dynamic organization of transposable elements (TEs) were identified, representing the major variation of the AvrPiz-t locus between different isolates. Moreover, TEs constitute 27.3% and 43.2% of the genomic contents of the AvrPiz-t-ZB15 and avrPiz-t-70-15 regions, respectively, indicating that TEs contribute largely to the organization and evolution of AvrPiz-t locus. The findings of this study suggest that M. oryzae could benefit in an evolutionary sense from the presence of active TEs in genes conferring avirulence and provide an ability to rapidly change and thus to overcome host R genes

Macrocytic Anemia And Mitochondriopathy Resulting From A Defect In Sideroflexin 4

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.935906914AHA; American Heart Association; American Society of Hematology; 6-FY09-289; March of Dimes Foundation; DK085217; NIH; National Institutes of Health; T32 HL007574; NIH; National Institutes of Health; F32 DK098866; NIH; National Institutes of Health; R01 GM61721; NIH; National Institutes of Health; R01 GM097136; NIH; National Institutes of Health; P01 HD032062; NIH; National Institutes of Health; R01 DK070838; NIH; National Institutes of Health; P01 HL032262; NIH; National Institutes of HealthVafai, S.B., Mootha, V.K., Mitochondrial disorders as windows into an ancient organelle (2012) Nature, 491, pp. 374-383Aslinia, F., Mazza, J.J., Yale, S.H., Megaloblastic anemia and other causes of macrocytosis (2006) Clin. Med. Res., 4, pp. 236-241Dimauro, S., Servidei, S., Zeviani, M., Dirocco, M., Devivo, D.C., Didonato, S., Uziel, G., Johnsen, S.D., Cytochrome c oxidase deficiency in Leigh syndrome (1987) Ann. Neurol., 22, pp. 498-506Yu, H.C., Sloan, J.L., Scharer, G., Brebner, A., Quintana, A.M., Achilly, N.P., Manoli, I., Schneck, U., An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1 (2013) Am. J. Hum. Genet., 93, pp. 506-514Gherasim, C., Lofgren, M., Banerjee, R., Navigating the B(12) road: Assimilation, delivery, and disorders of cobalamin (2013) J. Biol. Chem., 288, pp. 13186-13193Nyhan, W.L., Disorders of purine and pyrimidine metabolism (2005) Mol. Genet. Metab., 86, pp. 25-33Lieber, D.S., Calvo, S.E., Shanahan, K., Slate, N.G., Liu, S., Hershman, S.G., Gold, N.B., Berry, G.T., Targeted exome sequencing of suspected mitochondrial disorders (2013) Neurology, 80, pp. 1762-1770Calvo, S.E., Compton, A.G., Hershman, S.G., Lim, S.C., Lieber, D.S., Tucker, E.J., Laskowski, A., Jaffe, D.B., Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing (2012) Sci. Transl. Med., 4, pp. 18r-10Mayr, J.A., Haack, T.B., Graf, E., Zimmermann, F.A., Wieland, T., Haberberger, B., Superti-Furga, A., Baumgartner, M.R., Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome (2012) Am. J. Hum. Genet., 90, pp. 314-320Haack, T.B., Haberberger, B., Frisch, E.M., Wieland, T., Iuso, A., Gorza, M., Strecker, V., Herberg, U., Molecular diagnosis in mitochondrial complex 1 deficiency using exome sequencing (2012) J. Med. Genet., 49, pp. 277-283Isken, O., Maquat, L.E., The multiple lives of NMD factors: Balancing roles in gene and genome regulation (2008) Nat. Rev. Genet., 9, pp. 699-712Paw, B.H., Tieu, P.T., Kaback, M.M., Lim, J., Neufeld, E.F., Frequency of three Hex A mutant alleles among Jewish and non-Jewish carriers identified in a Tay-Sachs screening program (1990) Am. J. Hum. Genet., 47, pp. 698-705Farr, C.J., Saiki, R.K., Erlich, H.A., McCormick, F., Marshall, C.J., Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes (1988) Proc. Natl. Acad. Sci. USA, 85, pp. 1629-1633Paw, B.H., Moskowitz, S.M., Uhrhammer, N., Wright, N., Kaback, M.M., Neufeld, E.F., Juvenile GM2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase (1990) J. Biol. Chem., 265, pp. 9452-9457Pagliarini, D.J., Calvo, S.E., Chang, B., Sheth, S.A., Vafai, S.B., Ong, S.E., Walford, G.A., Chen, W.K., A mitochondrial protein compendium elucidates complex 1 disease biology (2008) Cell, 134, pp. 112-123Chen, W., Paradkar, P.N., Li, L., Pierce, E.L., Langer, N.B., Takahashi- Makise, N., Hyde, B.B., Paw, B.H., Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria (2009) Proc. Natl. Acad. Sci. USA, 106, pp. 16263-16268Fay, F.S., Taneja, K.L., Shenoy, S., Lifshitz, L., Singer, R.H., Quantitative digital analysis of diffuse and concentrated nuclear distributions of nascent transcripts, SC35 and poly(A) (1997) Exp. Cell Res., 231, pp. 27-37Chen, H.W., Rainey, R.N., Balatoni, C.E., Dawson, D.W., Troke, J.J., Wasiak, S., Hong, J.S., French, S.W., Mammalian polynucleotide phosphorylase is an intermembrane space Nase that maintains mitochondrial homeostasis (2006) Mol. Cell. Biol., 26, pp. 8475-8487Lieschke, G.J., Currie, P.D., Animal models of human disease: Zebrafish swim into view (2007) Nat. Rev. Genet., 8, pp. 353-367Cooney, J.D., Hildick-Smith, G.J., Shafizadeh, E., McBride, P.F., Carroll, K.J., Anderson, H., Shaw, G.C., Dalton, A.J., Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis (2013) Dev. Biol., 373, pp. 431-441Amigo, J.D., Yu, M., Troadec, M.B., Gwynn, B., Cooney, J.D., Lambert, A.J., Chi, N.C., Kaplan, J., Identification of distal cis- regulatory elements at mouse mitoferrin loci using zebrafish transgenesis (2011) Mol. Cell. Biol., 31, pp. 1344-1356Thon, J.N., Macleod, H., Begonja, A.J., Zhu, J., Lee, K.C., Mogilner, A., Hartwig, J.H., Italiano, Jr.J.E., Microtubule and cortical forces determine platelet size during vascular platelet production (2012) Nat Commun, 3, p. 852Pase, L., Layton, J.E., Kloosterman, W.P., Carradice, D., Waterhouse, P.M., Lieschke, G.J., MiR-451 regulates zebrafish erythroid maturation in vivo via its target gata2 (2009) Blood, 113, pp. 1794-1804Zhao, Y., Qin, W., Zhang, J.P., Hu, Z.Y., Tong, J.W., Ding, C.B., Peng, Z.G., Jiang, J.D., HCV IRES-mediated core expression in zebrafish (2013) PLoS ONE, 8, pp. e56985Ma, Y., Wu, M., Li, D., Li, X.Q., Li, P., Zhao, J., Luo, M.N., Ma, X., Embryonic developmental toxicity of selenite in zebrafish (Danio rerio) and prevention with folic acid (2012) Food Chem. Toxicol., 50, pp. 2854-2863Amigo, J.D., Ackermann, G.E., Cope, J.J., Yu, M., Cooney, J.D., Ma, D., Langer, N.B., Horsely, W., The role and regulation of friend of GATA-1 (FOG-1) during blood development in the zebrafish (2009) Blood, 114, pp. 4654-4663Bergmann, A.K., Campagna, D.R., McLoughlin, E.M., Agarwal, S., Fleming, M.D., Bottomley, S.S., Neufeld, E.J., Systematic molecular genetic analysis of congenital sideroblastic anemia: Evidence for genetic heterogeneity and identification of novel mutations (2010) Pediatr. Blood Cancer, 54, pp. 273-278Ganis, J.J., Hsia, N., Trompouki, E., De Jong, J.L., Dibiase, A., Lambert, J.S., Jia, Z., Sandstrom, R., Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR (2012) Dev. Biol., 366, pp. 185-194Yu, D., Dos Santos, C.O., Zhao, G., Jiang, J., Amigo, J.D., Khandros, E., Dore, L.C., Zhang, Z., MiR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta (2010) Genes Dev, 24, pp. 1620-1633Blanc, L., Ciciotte, S.L., Gwynn, B., Hildick-Smith, G.J., Pierce, E.L., Soltis, K.A., Cooney, J.D., Peters, L.L., Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis (2012) Proc. Natl. Acad. Sci. USA, 109, pp. 12099-12104Shah, D.I., Takahashi-Makise, N., Cooney, J.D., Li, L., Schultz, I.J., Pierce, E.L., Narla, A., Medlock, A.E., Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts (2012) Nature, 491, pp. 608-612Kornblum, C., Nicholls, T.J., Haack, T.B., Schöler, S., Peeva, V., Danhauser, K., Hallmann, K., Iuso, A., Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease (2013) Nat. Genet., 45, pp. 214-219Finsterer, J., Hematological manifestations of primary mitochondrial disorders (2007) Acta Haematol, 118, pp. 88-98Riley, L.G., Cooper, S., Hickey, P., Rudinger-Thirion, J., McKenzie, M., Compton, A., Lim, S.C., Giegé, R., Mutation of the mitochondrial tyrosyl- tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia - MLASA syndrome (2010) Am. J. Hum. Genet., 87, pp. 52-59Fellman, V., The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload (2002) Blood Cells Mol. Dis., 29, pp. 444-450Fleming, M.D., Campagna, D.R., Haslett, J.N., Trenor III, C.C., Andrews, N.C., A mutation in a mitochondrial transmembrane protein is responsible for the pleiotropic hematological and skeletal phenotype of flexed-tail (f/f) mice (2001) Genes Dev, 15, pp. 652-657Hegde, S., Lenox, L.E., Lariviere, A., Porayette, P., Perry, J.M., Yon, M., Paulson, R.F., An intronic sequence mutated in flexed-tail mice regulates splicing of Smad5 (2007) Mamm. Genome, 18, pp. 852-860Miyake, S., Yamashita, T., Taniguchi, M., Tamatani, M., Sato, K., Tohyama, M., Identification and characterization of a novel mitochondrial tricarboxylate carrier (2002) Biochem. Biophys. Res. Commun., 295, pp. 463-468Soranzo, N., Spector, T.D., Mangino, M., Kuhnel, B., Rendon, A., Teumer, A., Willenborg, C., Li, M., A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium (2009) Nat. Genet., 41, pp. 1182-1190Van Der Harst, P., Zhang, W., Mateo Leach, I., Rendon, A., Verweij, N., Sehmi, J., Paul, D.S., Li, X., Seventy-five genetic loci influencing the human red blood cell (2012) Nature, 492, pp. 369-375Ganesh, S.K., Zakai, N.A., Van Rooij, F.J., Soranzo, N., Smith, A.V., Nalls, M.A., Chen, M.H., Dehghan, A., Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium (2009) Nat. Genet., 41, pp. 1191-1198Foo, J.N., Liu, J.J., Tan, E.K., Whole-genome and whole-exome sequencing in neurological diseases (2012) Nat Rev Neurol, 8, pp. 508-517Bras, J., Guerreiro, R., Hardy, J., Use of nextgeneration sequencing and other whole-genome strategies to dissect neurological disease (2012) Nat. Rev. Neurosci., 13, pp. 453-46