Kiyosawa H, Lensch M W, Chance P F
Division of Neurology, The Children's Hospital of Phildelphia, Pennsylvania 19104, USA.
Hum Mol Genet. 1995 Dec;4(12):2327-34. doi: 10.1093/hmg/4.12.2327.
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 neuropathy type 1A (CMT1A) and deleted in hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A-REP repeat is proposed to mediate misalignment and unequal crossover resulting in reciprocal chromosomal rearrangements in CMT1A and HNPP. We have constructed a physical map of the proximal and distal CMT1A-REP repeats. Cloned fragments from CMT1A-REP repeat regions are used to determine the size of the repeats and assess regions of homology. The crossover breakpoints were mapped in series of 30 unrelated CMT1A patients and 22 unrelated HNPP patients. The CMT1A-REP repeat spans approximately 27 kilobase pairs and appears to be continuous. Locations of restriction enzyme sites are highly conserved for the proximal and distal CMT1A-REP repeats. All crossovers mapped within the CMT1A-REP repeat sequence and heterogeneity for breakpoint location demonstrated. Seventy-seven percent (40 to 52) of CMT1A and HNPP chromosomes contained breakpoints which mapped within a 7.9 kb interval, suggesting the presence of a possible 'hotspot'for recombination in CMT1A-REP. DNA sequence analysis for 4 kb of the interval containing the majority of crossovers revealed over 98% sequence identity between proximal and distal CMT1A-REP repeat sequences. Probes useful for molecular-based diagnosis of CMT1A and HNPP are described.
CMT1A-REP重复序列位于17号染色体p11.2 - 12区域的一个1.5兆碱基对（Mb）片段两侧，该片段在1A型夏科 - 马里 - 图斯神经病变（CMT1A）中发生重复，而在遗传性压力易感性周围神经病（HNPP）中发生缺失。有人提出CMT1A-REP重复序列介导错配和不等交换，从而导致CMT1A和HNPP中相互的染色体重排。我们构建了近端和远端CMT1A-REP重复序列的物理图谱。来自CMT1A-REP重复区域的克隆片段用于确定重复序列的大小并评估同源区域。在30名无亲缘关系的CMT1A患者和22名无亲缘关系的HNPP患者系列中绘制了交叉断点图谱。CMT1A-REP重复序列跨度约27千碱基对，似乎是连续的。近端和远端CMT1A-REP重复序列的限制性酶切位点位置高度保守。所有交叉均定位在CMT-1A-REP重复序列内，并显示出断点位置的异质性。77%（40至52）的CMT1A和HNPP染色体含有定位在7.9 kb区间内的断点，这表明在CMT1A-REP中可能存在一个重组“热点”。对包含大多数交叉的4 kb区间进行DNA序列分析，结果显示近端和远端CMT1A-REP重复序列之间的序列同一性超过98%。本文描述了可用于基于分子诊断CMT1A和HNPP的探针。
