Nature Genetics
5, 254 - 258 (1993)
doi:10.1038/ng1193-254
Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type IMing-yi Chung1, Laura P.W. Ranum1, Lisa A. Duvick1, Antonio Servadio2, Huda Y. Zoghbi2
& Harry T. Orr1
1Department of Laboratory Medicine and Pathology, and Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455, USA
2Department of Pediatrics, and Institute for Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030, USA Correspondence should be addressed to H.T.O. Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat on chromosome 6p. Normal alleles range from 19−36 repeats while SCA1 alleles contain 43−81 repeats. We now show that in 63% of paternal transmissions, an increase in repeat number is observed, whereas 69% of maternal transmissions showed no change or a decrease in repeat number. Sequence analysis of the repeat from 126 chromosomes reveals an interrupted repeat configuration in 98% of the unexpanded alleles but a contiguous repeat (CAG)n configuration in 30 expanded alleles from seven SCA1 families. This indicates that the repeat instability in SCA1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the SCA1 (CAG)n to expansion.
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