Human Molecular Genetics, Vol 6, 971-979, Copyright © 1997 by Oxford University Press
C Moutou, MC Vincent, V Biancalana and JL Mandel
In the fragile X syndrome, the transition from unmethylated moderate
expansions of the CGG repeat (premutations) to methylated large expansions
(full mutations) occurs only through maternal transmission. The risk of
such transition is highly correlated with the size of the maternal
premutation (PM), being very low for small PM alleles (approximately 60
repeats), to 100% for alleles above 100 repeats. The timing of this
transition was the object of much speculation. A postzygotic transition was
proposed as a preferred model, based on the observation that males with
full mutation (FM) have PM in sperm. Analysis of tissues from affected
fetuses, including additional data reported here, indicate that such a
putative postzygotic transition would have to occur very early in
embryogenesis and most likely before determination of germ cell lineage. At
least 15% of carriers of a FM show a significant proportion of white blood
cells carrying a PM (mutation mosaics). We performed a simulation study
showing that, if transition to FM is postzygotic, one should observe a much
higher proportion of such mosaics in offspring of mothers with small PMs.
This was compared with the actual pattern observed in 212 mutated offspring
of 112 PM carrier mothers. We found no effect of maternal PM size on
incidence of mosaicism in leucocytes. We propose that this is strong,
albeit indirect evidence against a postzygotic transition to FM. A
transition at an early morula stage (before day 3) cannot, however, be
formally excluded.
ARTICLES
Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic
Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine et CHRU, Strasbourg, France.
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