Meiotic instability associated with the CAGR1 trinucleotide repeat at 13q13.

Abstract

CAGR1 is a recently characterised polymorphic trinucleotide repeat localised to 13q13, which has been suggested as a possible candidate gene for neurological disorders that manifest genetic anticipation. To provide evidence in support of this hypothesis, a large number of chromosomes (n = 928) from patients with a wide variety of neurological diseases were screened for evidence of repeat expansion and meiotic instability. One person with a CAGR1 repeat number of 50 was identified (normal range 9-29). Subsequent molecular analyses of CAGR1 repeat number in additional family members showed meiotic instability of a (CAG)45 allele through three generations. While CAGR1 repeat number did not correlate with a readily discernible phenotype in this family, the finding of meiotic stability and mendelian inheritance of normal CAG alleles and meiotic instability of larger repeats fulfil several criteria thought essential for pathologically relevant mutations of this type. Thus, these data strengthen the hypothesis for a role of CAGR1 in the development of an as yet molecularly uncharacterised human neurological disease.