Date of Award
Doctor of Philosophy (PhD)
Dr. Darrell J. Tomkins
Roberts syndrome (RS) is a rare, recessive condition characterized by growth retardation, developmental delay and tetraphocomelia. Some RS patients (RS+), but not others (RS-), exhibit a "puffing" pf the constitutive heterochromatic regions of their chromosones (the "RS effect"). Cells from RS+ patients also show cellular hypersensitivity to DNA crosslinking agents such as mitomycin C (MMC). In the present study, correction of both the RS effect and MMC hypersensitivityin somatic cell hybrids between RS+ and normal lymphoblastoid cells (LCLs) supported the hypothesis of an association between the RS effect and mutagen sensitivity in RS+ cells. Somatic cell hybrids between two RS+ LCLs derived from patients with diverse ethnic backgrounds exhibited both the RS effect and MMC hypersensitivity indicating that these patients represent a single complementation group. Somatic cell hybrids between one of the RS+ and two different RS- LCLs demonstrated complete complementation of both the RS effect and MMC hypersensitivity indicating that these patiens represent a single complementation group. Somatic cell hybrids between one of the RS+ and two different RS- LCLs demonstrated complete complementation of both the RS effect and MMC hypersensitivity. These findings suggest that RS+ and RS- patients belong to different complementation groups.
Fanconi anaemia (FA) is another rare, recessive disorder characterized by growth retardation, developmental delay, limb abnormalities and progressive pancytopenia. Cells from FA pateints exhibit both chromosomal and celluar hypersensitivity to DNA crosslinking agents. A study of the sensitivity and mutanility of various LCLs by ethyl methanesulphonate (EMS) indicated an increased cellular sensitivity and decreased mutability of RS+ LCLs relative to control LCLs. RS-LCLs did not exhibit these phenomena. One FA LCL from complementation group A showed a slightly increased cellular sensitivity but normal mutability. These results suggest hypomutability by EMS may be associated with the RS effect and MMC hypersensitivity.
Somatic cell hybrids were made between one of the RS+ LCLs and an LCL from each of the four known FA complementation groups. Hybrids were examined for correction of MMC hypersensitivity, the RS effect and diepoxybutane-induced chromosome aberrations.
Complementation was observed in hybrids with FA LCLs from complementation groups A,B and D but incomplete correction of chromosomal and cellular sensitivities to crosslinking agents in RS+ x FA C hybrids suggested a genetic association.
Allingham-Hawkins, Diane Joan, "A Study of the Genetic Heterogeneity In Roberts Syndrome" (1993). Open Access Dissertations and Theses. Paper 2118.