Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat.
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.
Igarashi
S
S
Department of Neurology, Niigata University, Japan.
Takiyama
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Y
Cancel
G
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Rogaeva
E A
EA
Sasaki
H
H
Wakisaka
A
A
Zhou
Y X
YX
Takano
H
H
Endo
K
K
Sanpei
K
K
Oyake
M
M
Tanaka
H
H
Stevanin
G
G
Abbas
N
N
Dürr
A
A
Rogaev
E I
EI
Sherrington
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R
Tsuda
T
T
Ikeda
M
M
Cassa
E
E
Nishizawa
M
M
Benomar
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A
Julien
J
J
Weissenbach
J
J
Wang
G X
GX
Agid
Y
Y
St George-Hyslop
P H
PH
Brice
A
A
Tsuji
S
S
D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D017827:Machado-Joseph Disease / Q000208:ethnology / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D012306:Risk; D012737:Sex Factors; D018911:Trinucleotide Repeats / Q000235:genetics*