Clinical and cytological studies are proposed in six genetically determined human disorders: Bloom's syndrome (BS), Fanconi's anemia (FA), ataxia telangiectasia (AT), xeroderma pigmentosum (XP), Werner's syndrome (WS), and Robert's syndrome (RS). Developmental defects exist at the organismal and, or, cellular level in each syndrome: BS is characterized by severe intra- and extra-uterine growth deficiency and often by immunodeficiency; skeletal and renal abnormalities and marrow failure are present in FA; in AT immunodeficiency exists; neurological deficiencies occur in some complementation groups in XP; in WS many features of aging appear prematurely; growth deficiency and tetraphocomelia are features of RS. Growth distrurbances exist also in cultured cells from most of the disorders. A common cytogenetic feature of all six syndromes is chromosome instability and, with the exception of RS, an increased incidence of cancer. The chromosome instability in BS, FA, AT, and XP exists in the form of significantly increased numbers of broken and rearranged chromosomes occurring either spontaneously of following treatment with DNA damaging agents, while in RS premature separation of the heterochromatic chromosome regions occurs.
Specific aims of the proposed research are the following: (i) The clinical features and genetics of the six syndromes will be defined more fully. Affected families will be followed for years to come, determining particularly the incidence, age of onset, and types of cancer that occur in homo- and heterozygotes. (ii) The in vitro growth disturbances in cells from persons with the syndromes will be characterized looking particularly for a block in some cell cycle stage. (iii) The emergence, evolution, and expansion of clones of cell shaving mutated chromosome complements will be followed trying to correlate their presence with such clinical changes as the development of cancer and immunodeficiency. (iv) Evidence will be sought for genome instability in vivo by looking for an increased incidence of mutation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD004134-18
Application #
3310230
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1977-09-01
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
18
Fiscal Year
1985
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
German, James; Sanz, Maureen M; Ciocci, Susan et al. (2007) Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat 28:743-53
German, J (1997) Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93:100-6
Straughen, J; Ciocci, S; Ye, T Z et al. (1996) Physical mapping of the bloom syndrome region by the identification of YAC and P1 clones from human chromosome 15 band q26.1. Genomics 35:118-28
German, J; Ellis, N A; Proytcheva, M (1996) Bloom's syndrome. XIX. Cytogenetic and population evidence for genetic heterogeneity. Clin Genet 49:223-31
Ellis, N A; Groden, J; Ye, T Z et al. (1995) The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83:655-66
German, J (1995) Bloom's syndrome. Dermatol Clin 13:7-18
Ellis, N A; Lennon, D J; Proytcheva, M et al. (1995) Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells. Am J Hum Genet 57:1019-27
Ellis, N A; Roe, A M; Kozloski, J et al. (1994) Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome. Am J Hum Genet 55:453-60
Martin, R H; Rademaker, A; German, J (1994) Chromosomal breakage in human spermatozoa, a heterozygous effect of the Bloom syndrome mutation. Am J Hum Genet 55:1242-6
German, J; Roe, A M; Leppert, M F et al. (1994) Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci U S A 91:6669-73

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