Germinal Mosaicism

Cellular data, particularly regarding structures called telomeres, suggests that some of the cells from Hutchinson-Gilford patients are prone to early cell senescence. Telomeres are special DNA structures at the tips of the chromosomes. These telomeres gradually shorten over time, and this shortening is associated with some aspects of cellular aging. Skin fibroblasts from Hutchinson-Gilford patients have shorter than normal telomeres and consequently undergo early cell senescence. At birth, the mean telomere length of these children is equivalent to that of a normal eighty-five-year-old.

Introduction of human telomerase into such cells leads to reextension of the telomeres and results in normal immortalization of these progeric cell cultures. Clinical interventional studies using this strategy in humans are pending. Predictably, circulating lymphocytes of Hutchinson-Gilford children have normal telomere lengths, in keeping with their normal immune function. Research thus far suggests that progeria may not be so much a genetic disease as it is an "epigenetic mosaic disease." In progeria, this means that the genes are normal, but the abnormally short telomere length in only certain cells lines causes an abnormal pattern of gene expression. The senescent pattern of gene expression in specific tissues results in the observed clinical disease of progeria.

Although consistent with all known laboratory and clinical data, the actual genetic mechanisms that underlie Hutchinson-Gilford progeria are still uncertain and arguable (the gene for Werner's syndrome, however, has been cloned). The question of what causes progeria holds a fascination largely for what it may tell us about the course of aging itself. see also Aging and Life Span; Alzheimer's Disease; Disease, Genetics of; DNA Repair; Down Syndrome; Inheritance Patterns; Mosaicism; Telomere.

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