Beyond Trisomy 21: Phenotypic Variability in People with Down
Syndrome Explained by Further Chromosome Mis-segregation and
Mosaic Aneuploidy
Huntington Potter*
Department of Neurology, and Linda Crnic Institute for Down Syndrome, Rocky Mountain Alzheimer’s Disease Center, University of Colorado Anschutz Medical Center,

Abstract Phenotypic variability is a fundamental feature of the human population and is particularly evident among peoplewith Down syndrome and/or Alzheimer’s disease.
Herein, we review current theories of the potential origins of thisphenotypic variability and propose a novel mechanism based on our fiding that the, disrupts the mitotic Alzheimer’s disease-associatedAβ peptide, encoded on chromosome 21  spindle, induces  abnormal chromosome segregation, and produces mosaic populations  of aneuploid  cells in all tissues of people with Alzheimer’s disease and in mouse and cell models thereof.  Thus, individuals exposed to increased levels of the Aβ peptide should accumulate mosaic populations of aneuploid cells, with different chromosomes affected in different tissues and in different individuals. Specifially, people with Down syndrome, who express elevated levels of Aβ peptide throughout their lifetimes, would be predicted to accumulate additional types of aneuploidy,  beyond trisomy 21
and including changes in their trisomy 21 status, in mosaic cell populations.

Such mosaic aneuploidy would introduce a novel form of genetic variability that could potentially underlie much of the observed phenotypic variability among people with Down syndrome, and possibly also among people with Alzheimer’s disease.  This mosaic aneuploidy  theory of phenotypic variability in Down syndrome is supported  by several observations,  makes several testable predictions, and identifis a potential approach to reducing  the frequency of some of the most debilitating features of Down syndrome, including  Alzheimer’s disease.

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Publicacion: 23/07/2016