HD Lighthouse Contributing Editor's Comment: Up until recently researchers believed that mosaicism did not happen in Huntington's Disease. Early pathology studies of a small number of individuals found that the CAG count was the same in tissue samples from throughout their bodies. More recently, however, studies of the HD mice showed CAG expansion with age and in different parts of the body, so the researchers did more pathology studies from people and did find some mosaicism, although not as much as researchers have found in several other trinucleotide diseases. It's likely that this happens during a process where the cell is trying to repair the DNA or during transcription; recent research has shown that the cell does recognize that the extra repeats are abnormal and activates the DNA damage checkpoint pathway. We know that there is a bias toward increases in the CAG repeats in mosaicism. However, the case report below shows that contraction can also take place during the repair process. It may be that researchers can eventually find a way to promote the cell's ability to repair the HD gene.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 03 Oct 2004

Mosaicism of the CAG repeat sequence in the Huntington disease gene in a pair of monozygotic twins

We report on a pair of monozygotic twins belonging to a family segregating Huntington disease (HD). In routine DNA analysis of blood cells, they displayed three alleles of the CAG repeat sequence in the HD gene. Two different cell lines, carrying the normal allele together with either an expanded allele with 47 CAGs or an intermediate allele with 37 CAGs, were detected in blood and buccal epithelium from both twins. To our knowledge, this is the first case described of HD gene CAG repeat length mosaicism in blood cells. Haplotype analysis established that the 37 CAG allele most likely arose by contraction of the maternal 47 CAG allele. The contraction must have taken place postzygotically, possibly at a very early stage of development, and probably before separation of the twins. One of the twins has presented symptoms of HD for 4 years; his skin fibroblasts and hair roots carried only the cell line with the 47 CAG repeat allele. The other twin, who is without symptoms at present, displayed mosaicism in skin fibroblasts and hair roots. If the proportion of the two cell lines in the brain of each twin resembles that of their hair roots (another tissue originating from the ectoderm), the mosaicism in the unaffected twin would mean that only a part of his brain cells carried the expanded allele, which could explain why he, in contrast to his brother, has no symptoms at this time. Copyright 2004 Wiley-Liss, Inc.

Am J Med Genet. 2004 Sep 10;130A(2):154

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Source: Am J Med Genet. 2004 Sep 10;130A(2):154

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