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Estimating the stability of the proposed imprinted state of the fragile-X mutation when transmitted by females.
Follette PJ, Laird CD.
Department of Zoology, University of Washington, Seattle 98195.
Fragile-X
syndrome is a major cause of mental retardation in humans. The
X-inactivation imprinting model accounts for the unusual pattern of
inheritance and expression of this syndrome. According to this model,
the fragile-X mutation creates a local block to the attempted
reactivation of the mutant X chromosome prior to oogenesis. This local
block results in an "imprinted" fragile-X chromosome that is
deleterious in males and in females for whom this chromosome is
predominantly the active X chromosome. The imprinted state of the
fragile-X mutation is inferred to be stable when transmitted by an
imprinted female because the penetrance of the syndrome in sons of
affected females is estimated to be 1.0. To provide a more precise
estimate of the stability of the proposed fragile-X imprint, we have
analyzed published pedigrees that include restriction fragment length
polymorphism and cytogenetic data from sibships with mothers who are
interpreted as having an imprinted fragile-X allele. We conclude that
the fragile-X imprint was stable in 46 out of 48 female meioses. This
analysis leads to a preliminary estimate of about 96% for the stability
of the imprint through female meiosis. Two imprinted females had
progeny who appeared to be carriers of a nonimprinted fragile-X allele.
If this interpretation is correct, then reversion from the imprinted to
the nonimprinted state, or "erasure," can occasionally occur when the
mutant fragile-X allele is transmitted by an imprinted female. We
discuss the genetic and epigenetic significance of possible female
erasure. We request DNA and cytogenetic information from unpublished
pedigrees to quantify further the stability, during female meiosis, of
the proposed imprinted state of the mutant fragile-X allele.
PMID: 1346387 [PubMed - indexed for MEDLINE]
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