Molecular Mechanism of Esophageal Diffused Leiomyomatosis

我们研究了弥漫性平滑肌瘤病的分子机制以及IV型胶原与平滑肌细胞分化和增殖的关系，发现了DL/AS缺失，并首次鉴定了断裂点序列。结果表明，断裂点具有相同的序列，结果表明，DL/AS表型是由基因组重排引起的，并提出了在间隔序列III中可能有第三个基因参与平滑肌细胞增殖调控的可能性。r基因插入col 4a 6基因外显子2。小鼠具有生育能力，未显示任何明显的表型。存活1年以上的小鼠未发现食管弥漫性平滑肌瘤病及其他平滑肌器官肿瘤。本研究排除了col 4a 6基因缺失是DL的原因的可能性。我们现在通过将col 4a 6基因缺失小鼠与含有DL/AS患者部分基因组片段的转基因小鼠交配来研究其他可能性。此外，使用覆盖COL 4A 6基因的巨大内含子2的BAC重叠群进行外显子捕获。这些研究对于深入了解DL的发病机制和病因学具有重要意义。

We have investigated the molecular mechanism of diffused leiomyomatosis and the relationship of type IV collagen and smooth muscle cells differentiation and proliferation.We identified a DL/AS deletion and first characterization of the break point sequences. The results showed that the breakpoints share the same sequence, which is in turn closly homologous to the consensuses of topoisomerase I and II.The results implicate the genomic rearrangement responsible for the DL/AS phenotype and raise the possibility that there might be a third gene in interveaning sequence III that is involved in the regulation of smooth-muscle-cell proliferation.We have generated col4a6 null mice by introducing Neo^r gene into exon2 of col4a6 gene. The mice are fertile and did not show any obvious phenotype. Neither diffused leiomyomatosis in esophagus nor other tumors in smooth muscle organ were found in the mice which lived more than one year. This result exclude the possibility that deletion of col4a6 gene is a cause of DL.We are now investigating other possibilities by mating the col4a6 null mice and a transgemic mice which contains the partial genomic fragment delived5 from DL/AS patient. Also exon trapping was performed using a BAC contig which covers huge intron 2 of COL4A6 gene. These study were particularly relevant to the understunding of DL pathogenesis and its etiology.