Bengtsson U, Altherr M R, Wasmuth J J, Winokur S T
Department of Biological Chemistry, University of California, Irvine 92717.
Hum Mol Genet. 1994 Oct;3(10):1801-5. doi: 10.1093/hmg/3.10.1801.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat.
面肩肱型肌营养不良症（FSHD）是一种常染色体显性神经肌肉疾病。FSHD基因座与4号染色体长臂上最远端的遗传标记相关联。在大多数FSHD家族中，一种EcoRI片段长度多态性与该疾病共分离。在EcoRI片段内存在一个3.2 kb重复序列的串联阵列。该重复序列的完整拷贝缺失与该疾病相关。最近发现，3.2 kbp重复序列与人基因组中几个异染色质区域发生交叉杂交，DNA序列分析显示其与一类异染色质重复序列LSau具有高度同源性。在本报告中，我们证明3.2 kbp串联重复序列位于一个亚端粒序列附近，该亚端粒序列距离端粒重复序列（TTAGGG）n 5 - 14 kb。对线性延伸的DNA链进行直接视觉荧光杂交，能够将该亚端粒序列可视化为来自差异标记的3.2 kbp串联重复序列的较长信号串末端的一小串信号。此外，为支持我们的数据表明3.2 kbp重复序列紧邻4q端粒，我们证明了总人类DNA与同一区域缺乏杂交。我们的结果表明，在FSHD中被破坏的3.2 kbp重复序列串联阵列紧邻4q端粒，并且导致FSHD的基因可能位于串联重复序列的近端。
