Bloom syndrome

Identity

Atlas_Id	10002
Genes implicated in	BML
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

Clinics

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 (café 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)

Cytogenetics

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

Note	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 Name	BLM
Location	15q26.1

Protein
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)
Function	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

Mutations

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.

Bibliography

Bloom's syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition.

Ababou M, Dumaire V, Lécluse Y, Amor-Gué M

Oncogene. 2002 ; 21 (13) : 2079-2088.

PMID 11960380

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-Guéret M

Human mutation. 2000 ; 15 (6) : 584-585.

PMID 10862105

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-Guéret M

Cancer research. 2004 ; 64 (24) : 8954-8959.

PMID 15604258

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

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-Guéret M

Oncogene. 2000 ; 19 (23) : 2731-2738.

PMID 10851073

Molecular genetics of Bloom's syndrome.

Ellis NA, German J

Human molecular genetics. 1996 ; 5 Spec No : 1457-1463.

PMID 8875252

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

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-Guéret M

Human molecular genetics. 1997 ; 6 (9) : 1427-1434.

PMID 9285778

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

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

Bloom's syndrome. XX. The first 100 cancers.

German J

Cancer genetics and cytogenetics. 1997 ; 93 (1) : 100-106.

PMID 9062585

Syndromes of the head and neck.

Gorlin RJ, Cohen MM, Levin LS

Oxford Monogr Med Genet. 1990 ; 19 : 297-300.

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

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

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 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

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

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

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

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-Guéret M

Nucleic acids research. 2003 ; 31 (21) : 6272-6282.

PMID 14576316

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Citation

This paper should be referenced as such :

Amor-Guéret, M

Bloom syndrome

Atlas Genet Cytogenet Oncol Haematol. 2005;9(2):174-177.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/BLOID10002.html

History of this paper:

Huret, JL. Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. 1998;2(2):65-66.

http://documents.irevues.inist.fr/bitstream/handle/2042/37422/02-1998-BLO10002.pdf

Amor-Guéret, M. Bloom syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000;4(4):218-220.

http://documents.irevues.inist.fr/bitstream/handle/2042/37677/09-2000-BLO10002.pdf

External links

OMIM	210900
Orphanet	Bloom syndrome
MeSH	D001816
MedGen	D001816
UMLS	C0005859
ICD-10	Q82.2
HGMD	135698

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