Trinucleotide Repeat Expansion and Human Disease

Eleven human loci, responsible for nine diseases, exhibit an unprecedented form of mutation: the expansion of trinucleotide repeats. Normally polymorphic CGG/CCG or CAG/CTG repeats (means of approximately 20 triplets) are found enlarged to either 2-3 or 10-1000 times normal lengths. The smaller expansions are found within genes coding for polyglutamine and are associated with neurodegenerative diseases. The larger expansions are most commonly associated with chromosomal fragile sites and can be found isolated or in the untranslated regions of genes. Expanded alleles of all these loci exhibit remarkable meiotic instability, frequently lengthening upon transmission. Since the abnormal repeat length can be correlated with incomplete penetrance and/or variable expressivity, the elongation in subsequent generations explains the genetic anticipation in these disorders.