Chromosomal fragility associated with familial Alzheimer's disease.
To test whether chromosomal instability is associated with familial Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for analyzing DNA breakage because of its numerous markers and ease of selection in rodent-human hybrid cells. Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene with the selected HPRT gene in hybrid cells, indicating breakage between the markers. Lower cotransfer of the more distant X-linked gene, MIC-2, was statistically significant in this kindred, but not in other patients with familial Alzheimer's disease. The distance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a "hot spot" for breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease. The somatic cell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced by the Alzheimer defect. A hypothesis implicating a candidate gene, C1-THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.
Ettinger
S
S
Department of Medicine, Cornell University Medical College, New York, NY 10021.
Weksler
M E
ME
Zhou
X
X
Blass
J
J
Szabo
P
P
D000071443:12E7 Antigen; D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D015703:Antigens, CD; D015815:Cell Adhesion Molecules / Q000235:genetics; D002872:Chromosome Deletion; D002873:Chromosome Fragility; D002874:Chromosome Mapping; D008040:Genetic Linkage; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D014960:X Chromosome
D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D005954:Glucosephosphate Dehydrogenase; D007041:Hypoxanthine Phosphoribosyltransferase