title: Recombination hot spot in a 3.2-kb region of the Charcot-Marie-Tooth type 1A repeat sequences: new tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie-Tooth type 1A. French CMT Collaborative Research Group.
abstract: Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP) are autosomal dominant neuropathies, associated, respectively, with duplications and deletions of the same 1.5-Mb region on 17p11.2-p12. These two rearrangements are the reciprocal products of an unequal meiotic crossover between the two chromosome 17 homologues, caused by the misalignment of the CMT1A repeat sequences (CMT1A-REPs), the homologous sequences flanking the 1.5-Mb CMT1A/HNPP monomer unit. In order to map recombination breakpoints within the CMT1A-REPs, a 12.9-kb restriction map was constructed from cloned EcoRI fragments of the proximal and distal CMT1A-REPs. Only 3 of the 17 tested restriction sites were present in the proximal CMT1A-REP but absent in the distal CMT1A-REP, indicating a high degree of homology between these sequences. The rearrangements were mapped in four regions of the CMT1A-REPs by analysis of 76 CMT1A index cases and 38 HNPP patients, who where unrelated. A hot spot of crossover breakpoints, located in a 3.2-kb region, accounted for three-quarters of the rearrangements, detected after EcoRI/SacI digestion, by the presence of 3.2-kb and 7.8-kb junction fragments in CMT1A and HNPP patients, respectively. These junction fragments, which can be detected on classical Southern blots, permit molecular diagnosis. Other rearrangements can also be detected by gene dosage on the same Southern blots.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Lopes
authors.forename: E
authors.initials: E
authors.lastname: LeGuern
authors.forename: R
authors.initials: R
authors.lastname: Gouider
authors.forename: S
authors.initials: S
authors.lastname: Tardieu
authors.forename: N
authors.initials: N
authors.lastname: Abbas
authors.forename: N
authors.initials: N
authors.lastname: Birouk
authors.forename: M
authors.initials: M
authors.lastname: Gugenheim
authors.forename: P
authors.initials: P
authors.lastname: Bouche
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
authors.forename: A
authors.initials: A
authors.lastname: Brice
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D003434:Crossing Over, Genetic; D015698:Genomic Library; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping