Dynamic mutations: where are they now?

Abstract

Dynamic mutations are those caused by the expansion of existing polymorphic DNA repeat sequences beyond a copy number threshold. These genetic mutations can give rise to dominant, recessive or X-linked disorders, dependent upon the location of the repeat sequence with respect to the genes that are affected by the expansion. The distinguishing feature of these mutations is their instability, which is a function of the copy number of repeats and can occur in either meiosis or mitosis. For some of the resultant disorders there is a relationship between repeat copy number and age-at-onset and/or severity ofsymptoms ofthe disease. For this reason much effort is now focused on identifying the pathogenic pathways from the mutation to the disease symptoms in the hope of finding means of delaying onset, slowing progression or even preventing symptoms ofthe disease. The growing list ofneurodegenerative and neuromuscular diseases caused by dynamic mutations includes Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), a number of spinocerebellar ataxias (SCAs), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophy Type 1 and 2 (DM1 and 2), Huntington's disease-like 2 (HDL-2), Friedrich's ataxia (FRDA), Fragile X associated tremor ataxia syndrome (FXTAS), Fragile XE (FRAXE) and Fragile XA (FRAXA). This chapter aims to give a brief overview of what is currently known about each disease and the mechanisms underlying pathogenesis.