H. Kiyosawa et al., ANALYSIS OF THE CMT1A-REP REPEAT - MAPPING CROSSOVER BREAKPOINTS IN CMT1A AND HNPP, Human molecular genetics, 4(12), 1995, pp. 2327-2334
The CMT1A-REP repeat sequence flanks a 1.5 megabase pair (Mb) segment
of chromosome 17p11.2-12 which is duplicated in Charcot-Marie-Tooth ne
uropathy type 1A (CMT1A) and deleted in hereditary neuropathy with lia
bility to pressure palsies (HNPP). The CMT1A-REP repeat is proposed to
mediate misalignment and unequal crossover resulting in reciprocal ch
romosomal rearrangements in CMT1A and HNPP. We have constructed a phys
ical map of the proximal and distal CMT1A-REP repeats, Cloned fragment
s from CMT1A-REP repeat regions were used to determine the size of the
repeats and to assess regions of homology. The crossover breakpoints
were mapped in a series of 30 unrelated CMT1A patients and 22 unrelate
d HNPP patients, The CMT1A-REP repeat spans approximately 27 kilobase
pairs and appears to be continuous. Locations of restriction enzyme si
tes are highly conserved for the proximal and distal CMT1A-REP repeats
. All crossovers mapped within the CMT1A-REP repeat sequence and heter
ogeneity for breakpoint location was demonstrated. Seventy-seven perce
nt (40 of 52) of CMT1A and HNPP chromosomes contained breakpoints whic
h mapped within a 7.9 kb interval, suggesting the presence of a possib
le 'hotspot' for recombination in CMT1A-REP. DNA sequence analysis for
4 kb of the interval containing the majority of crossovers revealed o
ver 98% sequence identity between proximal and distal CMT1A-REP repeat
sequences. Probes useful for molecular-based diagnosis of CMT1A and H
NPP are described.