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Chromosomal fragility associated with familial Alzheimer's disease
Author(s) -
Ettinger Susan,
Weksler Marc E.,
Zhou Xianting,
Blass John,
Szabo Paul
Publication year - 1994
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410360211
Subject(s) - alzheimer's disease , genetics , biology , chromosome instability , disease , degenerative disease , gene , chromosome , pathology , medicine , central nervous system disease , neuroscience
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, C 1 ‐THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.