Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I.
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.
Chung
M Y
MY
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455.
Ranum
L P
LP
Duvick
L A
LA
Servadio
A
A
Zoghbi
H Y
HY
Orr
H T
HT
D001483:Base Sequence; D002460:Cell Line; D002896:Chromosomes, Human, Pair 6; D004247:DNA; D017931:DNA Primers; D005799:Genes, Dominant; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D012091:Repetitive Sequences, Nucleic Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics*
D017931:DNA Primers; D004247:DNA