Bloom syndrome

2005-02-01   Mounira Amor-Guéret 

Institut Curie - Section de Recherche, UMR 2027 CNRS, Bâtiment 110, Centre Universitaire, F-91405 Orsay Cedex, France

Identity

Name

Bloom syndrome

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
Atlas Image
micronuclei (left); sister chromatid exchange (right) in a normal subject (herein: 19 SCE, instead of the hundred found in Bloom, see below) - Editor

Omim

210900

Mesh

D001816

Orphanet

125 Bloom syndrome

Umls

C0005859

Clinics

Note

168 cases have been registered in the Blooms 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 Blooms); 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 condition

  • 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.
    • Atlas Image
    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

    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

    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.

    To be noted

    Hgmd

    135698 BLM

    Bibliography

    Pubmed IDLast YearTitleAuthors