Human Molecular Genetics, Vol 7, 141-148, Copyright © 1998 by Oxford University Press
J Lopes, N Ravise, A Vandenberghe, F Palau, V Ionasescu, M Mayer, N Levy, N Wood, N Tachi, P Bouche, P Latour, M Ruberg, A Brice and E LeGuern
The molecular mechanism resulting in the duplication or deletion of a 1.5
Mb region of 17p11.2-p12, associated, respectively, with Charcot-
Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to
pressure palsies (HNPP), has been proposed to be an unequal crossing- over
during meiosis between the two chromosome 17 homologues generated by
misalignment of the proximal and distal CMT1A-REP repeats, two homologous
sequences flanking the 1.5 Mb CMT1A/HNPP monomer unit. In a recent study of
a large series of de novo cases of CMT1A and HNPP, two distinct
sex-dependent mechanisms were identified. Rearrangements of paternal
origin, essentially duplications, were indeed generated by unequal meiotic
crossing-over between the two chromosome 17 homologues, but duplications
and deletions of maternal origin resulted from an intrachromosomal process,
either unequal sister chromatid exchange or, in the case of deletion,
excision of an intrachromatidal loop. In order to determine how these
recombinations occur, 24 de novo crossover breakpoints were localized
within the 1.7 kb rearrangement hot spot by comparing the sequences of the
parental CMT1A-REPs with the chimeric copy in affected offspring. Nineteen
out of 21 paternal crossovers were found in a 741 bp hot spot. All the
breakpoints of maternal origin (n = 3), however, were located outside this
interval, but in closely flanking sequences, supporting the hypothesis that
two distinct sex- dependent mechanisms are involved. Several putative
recombination promoting sequences in the hot spot, which are rare or absent
in the surrounding 7.8 kb, were identified.
ARTICLES
Fine mapping of de novo CMT1A and HNPP rearrangements within CMT1A-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination
INSERM U289, 9Service d'Exploration Fonctionnelles Neurologiques and 10Federation de Neurologie, Hopital de la Salpetriere, 75651 Paris cedex 13, France.
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