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Bloom syndrome


Atlas_Id 10002
Inheritance autosomal recessive; frequency is about 2/105 newborns in Ashkenazi Jews and in the Japanese (founder effect: affected persons descent from a common ancestor); much rarer otherwise
  micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see below) - Editor


Note 168 cases have been registered in the Bloom's syndrome Registry by James German; BS patients are predisposed to all types of cancer observed in the general population; thus, BS is a model of initiation and promotion of cancer, and highligths internal causes/processes of cancers
Phenotype and clinics - phenotypic spectrum variable.
- growth : dwarfism: intrauterine growth retardation; birth weight: below 2.3 kg; mean length: 44 cm; adult length < 145 cm.
- skin: hyperpigmented (cafÈ au lait) spots; hypopigmented areas; sun sensitive telangiectatic erythema; in butterfly configuration across the face: resembles lupus erythematous
- head: microcephaly; dolichocephaly; narrow face; prominent nose and/or ears; characteristic high-pitched voice
- normal intelligence
- immune deficiency --> frequent infections (may be life-threatening)
- other: myocardopathy; hypogonadism in male patients; hypertriglyceridemia
Neoplastic risk
  • nearly half of patients have had at least one cancer (10% of whom having had more than one primary cancer, which is quite characteristic of Bloom's); mean age at first cancer onset: 25 yrs (range: 2-49 yrs)
  • acute leukaemias (ALL and ANLL) in 15 % of cases; lymphomas in 15 % as well; these occur mainly before the thirties
  • carcinomas (of a wide variety) occur in 30 % of cases, mainly after the age of 20 yrs
  • benign tumours (10%)
  • Evolution major medical complications apart from cancers are : chronic lung disease, and diabetes mellitus (in 10 %)
    Prognosis 1/3 of patients are dead at mean age 24 yrs (oldest died at 49 yrs, youngest died before 1 yr) and the mean age of the 2/3 remaining alive patients is 22 yrs (range: 4-46 yrs)


    Inborn conditions
  • chromatid/chromosome breaks; triradial and quadriradial figures, in particular symetrical quadriradial configuration involving homologous chromosomes (Class I qr), which are pathognomonic and which may be due to a mitotic crossing-over; micronuclei .
  • diagnosis is on the (pathognomonic) highly elevated spontaneous sister chromatid exchange rate (90 SCE per cell; more than 10 times what is normally found); in some persons a minor population of low SCE cells exists, suggesting a recombination event between maternal and paternal alleles (with different mutations), giving rise to a wild type functional gene; this allowed to localize the gene in a very elegant strategy.
  • heterozygotes are not detectable by cytogenetic studies.
      sister chromatid exchange in a normal subject (left) and in a Bloom syndrome patient (right) (from: Mounira Amor-Guéret)

    Other findings

  • slowing of the cell cycle (lenthening of the G1 and S phases)
  • spontaneous mutation rate 10 times higher than normal cells
  • Genes involved and Proteins

    Complementation groups no complementation group
    Gene NameBLM
    Location 15q26.1
    Description 1417 amino acids; contains one ATP binding site, one DEAH box, and two putative nuclear localization signals
    Expression accumulates to high levels in S phase of the cell cycle, persists in G2/M and sharply declines in G1; hyperphoshorylated in mitosis
    Localisation nuclear (PML nuclear bodies and nucleolus)
  • 3-5 DNA helicase; probable role in DNA replication and double-strand break repair
  • Preferred substrates: G-quadruplex DNA, D-loops structures and X-junctions. Recombinant protein promotes ATP-dependent branch migration of Hollyday junctions.
  • participates in a supercomplex of BRCA1-associated proteins named BASC (BRCA1-Associated genome Surveillance Complex) and in a complex named BRAFT (BLM, RPA, FA, Topoisomerase IIIalpha) containing five of the Fanconia Anemia (FA) complementation group proteins (FANCA, FANCG, FANCC, FANCE and FANCF).
  • Interacts physically and/or functionally with p53, 53BP1,WRN, MLH1, RAD51, TRF2, ligase IV, FEN1
  • Associated with telomeres and ribosomal DNA repeats.
  • Phosphorylated in mitotic cells through the cdc2 pathway, and in response to DNA damaging agents.
  • Homology with the RecQ helicases
    Germinal five BLM mutations introducing amino acid substitutions and four BLM mutations introducing premature nonsense codons into the coding sequence have been described to date; one BLM mutation consisting in a 6 bp deletion accompanied by a 7 bp insertion at nucleic acid position 2281 is common in patients from Ashkenazi Jewish ancestry, leading to a truncated protein of 739 amino acids in length; two BLM mutations, 631delCAA and 1610insA were detected in japanese patients.

    External links

    OrphanetBloom syndrome


    Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients.
    German J
    American journal of human genetics. 1969 ; 21 (2) : 196-227.
    PMID 5770175
    Syndromes of the head and neck.
    Gorlin RJ, Cohen MM, Levin LS
    Oxford Monogr Med Genet. 1990 ; 19 : 297-300.
    The Bloom's syndrome gene product is homologous to RecQ helicases.
    Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J
    Cell. 1995 ; 83 (4) : 655-666.
    PMID 7585968
    Molecular genetics of Bloom's syndrome.
    Ellis NA, German J
    Human molecular genetics. 1996 ; 5 Spec No : 1457-1463.
    PMID 8875252
    Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome.
    Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Guˆ©ret M
    Human molecular genetics. 1997 ; 6 (9) : 1427-1434.
    PMID 9285778
    Bloom's syndrome. XX. The first 100 cancers.
    German J
    Cancer genetics and cytogenetics. 1997 ; 93 (1) : 100-106.
    PMID 9062585
    BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal.
    Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N
    Biochemical and biophysical research communications. 1997 ; 240 (2) : 348-353.
    PMID 9388480
    The Bloom's syndrome gene product is a 3'-5' DNA helicase.
    Karow JK, Chakraverty RK, Hickson ID
    The Journal of biological chemistry. 1997 ; 272 (49) : 30611-30614.
    PMID 9388193
    The Bloom's syndrome helicase unwinds G4 DNA.
    Sun H, Karow JK, Hickson ID, Maizels N
    The Journal of biological chemistry. 1998 ; 273 (42) : 27587-27592.
    PMID 9765292
    PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1.
    Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss JF 3rd, Maul GG
    The Journal of cell biology. 1999 ; 147 (2) : 221-234.
    PMID 10525530
    ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation.
    Ababou M, Dutertre S, Lˆ©cluse Y, Onclercq R, Chatton B, Amor-Guˆ©ret M
    Oncogene. 2000 ; 19 (52) : 5955-5963.
    PMID 11146546
    Identification of a novel BLM missense mutation (2706T>C) in a Moroccan patient with Bloom's syndrome.
    Barakat A, Ababou M, Onclercq R, Dutertre S, Chadli E, Hda N, Benslimane A, Amor-Guˆ©ret M
    Human mutation. 2000 ; 15 (6) : 584-585.
    PMID 10862105
    Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase.
    Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Guˆ©ret M
    Oncogene. 2000 ; 19 (23) : 2731-2738.
    PMID 10851073
    The Bloom's syndrome gene product promotes branch migration of holliday junctions.
    Karow JK, Constantinou A, Li JL, West SC, Hickson ID
    Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (12) : 6504-6508.
    PMID 10823897
    Binding and melting of D-loops by the Bloom syndrome helicase.
    van Brabant AJ, Ye T, Sanz M, German III JL, Ellis NA, Holloman WK
    Biochemistry. 2000 ; 39 (47) : 14617-14625.
    PMID 11087418
    BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.
    Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J
    Genes & development. 2000 ; 14 (8) : 927-939.
    PMID 10783165
    Nuclear structure in normal and Bloom syndrome cells.
    Yankiwski V, Marciniak RA, Guarente L, Neff NF
    Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (10) : 5214-5219.
    PMID 10779560
    Regulation and localization of the Bloom syndrome protein in response to DNA damage.
    Bischof O, Kim SH, Irving J, Beresten S, Ellis NA, Campisi J
    The Journal of cell biology. 2001 ; 153 (2) : 367-380.
    PMID 11309417
    The Bloom syndrome protein interacts and cooperates with p53 in regulation of transcription and cell growth control.
    Garkavtsev IV, Kley N, Grigorian IA, Gudkov AV
    Oncogene. 2001 ; 20 (57) : 8276-8280.
    PMID 11781842
    The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair.
    Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J
    The Journal of biological chemistry. 2001 ; 276 (32) : 30031-30035.
    PMID 11325959
    The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases.
    Mohaghegh P, Karow JK, Brosh Jr RM Jr, Bohr VA, Hickson ID
    Nucleic acids research. 2001 ; 29 (13) : 2843-2849.
    PMID 11433031
    Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1.
    Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I
    Nucleic acids research. 2001 ; 29 (21) : 4378-4386.
    PMID 11691925
    Functional interaction of p53 and BLM DNA helicase in apoptosis.
    Wang XW, Tseng A, Ellis NA, Spillare EA, Linke SP, Robles AI, Seker H, Yang Q, Hu P, Beresten S, Bemmels NA, Garfield S, Harris CC
    The Journal of biological chemistry. 2001 ; 276 (35) : 32948-32955.
    PMID 11399766
    Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51.
    Wu L, Davies SL, Levitt NC, Hickson ID
    The Journal of biological chemistry. 2001 ; 276 (22) : 19375-19381.
    PMID 11278509
    Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition.
    Ababou M, Dumaire V, Lˆ©cluse Y, Amor-Guˆ©ret M
    Oncogene. 2002 ; 21 (13) : 2079-2088.
    PMID 11960380
    Increased error-prone non homologous DNA end-joining--a proposed mechanism of chromosomal instability in Bloom's syndrome.
    Gaymes TJ, North PS, Brady N, Hickson ID, Mufti GJ, Rassool FV
    Oncogene. 2002 ; 21 (16) : 2525-2533.
    PMID 11971187
    The BLM helicase is necessary for normal DNA double-strand break repair.
    Langland G, Elliott J, Li Y, Creaney J, Dixon K, Groden J
    Cancer research. 2002 ; 62 (10) : 2766-2770.
    PMID 12019152
    Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.
    Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA
    The Journal of biological chemistry. 2002 ; 277 (43) : 41110-41119.
    PMID 12181313
    The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis.
    Stavropoulos DJ, Bradshaw PS, Li X, Pasic I, Truong K, Ikura M, Ungrin M, Meyn MS
    Human molecular genetics. 2002 ; 11 (25) : 3135-3144.
    PMID 12444098
    Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins.
    von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM Jr, Hickson ID, Bohr VA
    The Journal of biological chemistry. 2002 ; 277 (24) : 22035-22044.
    PMID 11919194
    The processing of Holliday junctions by BLM and WRN helicases is regulated by p53.
    Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM Jr, Karmakar P, Bohr VA, Harris CC
    The Journal of biological chemistry. 2002 ; 277 (35) : 31980-31987.
    PMID 12080066
    A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.
    Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W
    Molecular and cellular biology. 2003 ; 23 (10) : 3417-3426.
    PMID 12724401
    Possible anti-recombinogenic role of Bloom's syndrome helicase in double-strand break processing.
    Onclercq-Delic R, Calsou P, Delteil C, Salles B, Papadopoulo D, Amor-Guˆ©ret M
    Nucleic acids research. 2003 ; 31 (21) : 6272-6282.
    PMID 14576316
    BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination.
    Sengupta S, Linke SP, Pedeux R, Yang Q, Farnsworth J, Garfield SH, Valerie K, Shay JW, Ellis NA, Wasylyk B, Harris CC
    The EMBO journal. 2003 ; 22 (5) : 1210-1222.
    PMID 12606585
    Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase.
    Schawalder J, Paric E, Neff NF
    BMC cell biology. 2003 ; 4 : page 15.
    PMID 14577841
    Relatively common mutations of the Bloom syndrome gene in the Japanese population.
    Kaneko H, Isogai K, Fukao T, Matsui E, Kasahara K, Yachie A, Seki H, Koizumi S, Arai M, Utunomiya J, Miki Y, Kondo N
    International journal of molecular medicine. 2004 ; 14 (3) : 439-442.
    PMID 15289897
    A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint.
    Bayart E, Grigorieva O, Leibovitch S, Onclercq-Delic R, Amor-Guˆ©ret M
    Cancer research. 2004 ; 64 (24) : 8954-8959.
    PMID 15604258
    Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest.
    Sengupta S, Robles AI, Linke SP, Sinogeeva NI, Zhang R, Pedeux R, Ward IM, Celeste A, Nussenzweig A, Chen J, Halazonetis TD, Harris CC
    The Journal of cell biology. 2004 ; 166 (6) : 801-813.
    PMID 15364958
    Genetic interactions between BLM and DNA ligase IV in human cells.
    So S, Adachi N, Lieber MR, Koyama H
    The Journal of biological chemistry. 2004 ; 279 (53) : 55433-55442.
    PMID 15509577
    Human Bloom protein stimulates flap endonuclease 1 activity by resolving DNA secondary structure.
    Wang W, Bambara RA
    The Journal of biological chemistry. 2005 ; 280 (7) : 5391-5399.
    PMID 15579905
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    Written02-1998Jean-Loup Huret
    Updated09-2000Mounira Amor-Guéret
    Updated02-2005Mounira Amor-Guéret


    This paper should be referenced as such :
    Amor-Guéret M
    Bloom syndrome;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version :
    History of this paper:
    Atlas Genet Cytogenet Oncol Haematol. February 2005
    Atlas Genet Cytogenet Oncol Haematol. February 2005

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    indexed on : Wed Jun 17 15:19:31 CEST 2015

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