Molecular Mechanism of Esophageal Diffused Leiomyomatosis

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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.