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Abstract and Introduction
Abstract
Huntington's disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. Although the variation in age at onset is partly explained by the lengths of the expanded repeat, the unexplained variation is heritable, emphasizing the role of the so-called genetic background on disease expression. Identification of modifier genes can confirm intracellular pathways already suspected to be involved in pathophysiological processes related to HD pathogenesis, but it may also point to completely new pathways and processes that have not yet been considered. Most importantly, confirmed modifier genes provide new targets for the development of therapies. Up to now, a wide range of susceptible HD modifier genes related to different biochemical pathways has been examined. On the basis of the published literature in this field, this review provides an overview of HD modifiers and integrates them into selected pathophysiology aspects.
Introduction
Differences in genetic variation, environmental factors and epigenetic patterns between individuals contribute to phenotypic variation and disease susceptibility. Yet, their relative effects are difficult to determine, especially since most complex traits are controlled by many genetic variations of very small effect. Detecting genetic and nongenetic factors underlying the observed variability of monogenic disease manifestation is, however, a promising approach. Here, disease variability in patients bearing the same mutations emphasizes the role of genetic background and may also reveal environmental influences. Modifier variations that segregate independently from the primary mutation can influence penetrance, age at onset (AO), progression or severity of disease.
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