Founders and CAG repeats: cause or effect?

Abstract

Many neurodegenerative diseases are caused by expansions in DNA sequences called trinucleotide repeats.1-3 Huntington’s disease (HD), dentatorubropallidoluysian atrophy, and most of the autosomal dominant cerebellar ataxias (ADCAs) are caused by expansions in CAG repeat sequences that code for a string of glutamine residues at the amino acid level. These conditions are not gene knockouts, but rather toxic gain of function mutations caused by the translation of the CAG repeat into a longer than normal stretch of polyglutamines.1,3 A major feature of trinucleotide repeat diseases is the instability of the CAG repeat during germline transmission from parent to child—a characteristic that underlies the decrease in age at onset in successive generations (anticipation) observed in families.1,3 Spinocerebellar ataxia type 6 (SCA6) is a CAG repeat disorder that differs both clinically and molecularly from the other known SCAs.4 Patients with the SCA6 expansion can have at least three different syndromes: episodic ataxia type 2, ADCA I (cerebellar ataxia plus brainstem or long tract degeneration), or ADCA III (pure cerebellar ataxia).5,6 SCA6 is also unusual because the CAG expansion occurs in a CACNA1A calcium channel gene, making SCA6 the only SCA in which the gene and its function are known.4 The number of CAG expansions observed in SCA6 patients is much less variable and is within the normal range for stable, nonpathogenic repeats in …