Journal Article

Fine mapping of <i>de novo</i> CMT1A and HNPP rearrangements within CMTIA-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination

Judith Lopes, Nicole Ravisé, Antoon Vandenberghe, Francisco Palau, Victor Ionasescu, Michelle Mayer, Nicolas Lévy, Nicholas Wood, Nobutada Tachi, Pierre Bouche, Philippe Latour, Merle Ruberg, Alexis Brice and Eric LeGuern

in Human Molecular Genetics

Volume 7, issue 1, pages 141-148
Published in print January 1998 | ISSN: 0964-6906
Published online January 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.1.141
Fine mapping of de novo CMT1A and HNPP rearrangements within CMTIA-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination

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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 sexdependent 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.

Journal Article.  4520 words.  Illustrated.

Subjects: Genetics and Genomics

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