Abstract

This is the second revision of a competing renewal of a project which now focuses upon the origin and mechanism behind the recurrent 11;22 translocation in humans. This is the only recurrent, non-Robertsonian constitutional translocation in humans which gives rise to the supernumerary der(22)t(11;22) syndrome. Also, such 11;22 translocations have also been implicated in Ewing's sarcoma and, perhaps, in other tumors as well.
Five specific aims are now proposed. The first will be to isolate and characterize, including sequencing, the 11;22 breakpoint of the der(22) and der(11) of a translocation carrier.
The second aim will be to examine at a molecular level the breakpoints of other t(11;22) families and examine the aggregated breakpoint sequences for specific motifs or sequence patterns.
The third aim will be to examine the 22q11.23 breakpoint sequence cluster, identified in 11;22 translocations, with other translocations involving this specific location of chromosome 22.
The fourth aim will address the origin of the apparent 3:1 meiotic segregation seen in unbalanced offspring, where adjacent I segregation would be expected. The various mechanisms will be tested by marker segregation in t(11;22) families.
The final aim will be to examine the physical location and arrangement of chromosomes 11 and 22 in both meiosis and mitosis to gain additional clues toward the reason for this recurrent form of rearrangement.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039926-14
Application #
2894631
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Pelroy, Richard
Project Start
1985-01-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Kato, Takema; Franconi, Colleen P; Sheridan, Molly B et al. (2014) Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation. Cancer Genet 207:133-40
Bloch, Mercedes; Leonard, Anissa; Diplas, Andreas A et al. (2014) Further phenotype description, genotype characterization in patients with de novo interstitial deletion on 2p23.2-24.1. Am J Med Genet A 164A:1789-94
Inagaki, Hidehito; Ohye, Tamae; Kogo, Hiroshi et al. (2013) Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations. Nat Commun 4:1592
Kato, Takema; Kurahashi, Hiroki; Emanuel, Beverly S (2012) Chromosomal translocations and palindromic AT-rich repeats. Curr Opin Genet Dev 22:221-8
Vorstman, J A S; van Daalen, E; Jalali, G R et al. (2011) A double hit implicates DIAPH3 as an autism risk gene. Mol Psychiatry 16:442-51
Tong, Maoqing; Kato, Takema; Yamada, Kouji et al. (2010) Polymorphisms of the 22q11.2 breakpoint region influence the frequency of de novo constitutional t(11;22)s in sperm. Hum Mol Genet 19:2630-7
Sheridan, Molly B; Kato, Takema; Haldeman-Englert, Chad et al. (2010) A palindrome-mediated recurrent translocation with 3:1 meiotic nondisjunction: the t(8;22)(q24.13;q11.21). Am J Hum Genet 87:209-18
Carter, Melissa T; Barrowman, Nicholas J; St Pierre, Stephanie A et al. (2010) Risk of breast cancer not increased in translocation 11;22 carriers: analysis of 80 pedigrees. Am J Med Genet A 152A:212-4
Kurahashi, H; Inagaki, H; Ohye, T et al. (2010) The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangements. Clin Genet 78:299-309
Ohye, Tamae; Inagaki, Hidehito; Kogo, Hiroshi et al. (2010) Paternal origin of the de novo constitutional t(11;22)(q23;q11). Eur J Hum Genet 18:783-7

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