Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly

作者：Laura A. Lettice, Taizo Horikoshi, Simon J. H. Heaney, Marijke J. van Baren, Herma C. van der Linde, Guido J. Breedveld, Marijke Joosse, Nurten Ayse Akarsu, Ben A. Oostra, Naoto Endo, Minoru Shibata, Mikio Suzuki, Eiichi Takahashi, Toshikatsu Shinka, Yutaka Nakahori, Dai Ayusawa, Kazuhiko Nakabayashi, Stephen W. Scherer, Peter Heutink, Robert E. Hill, Sumihare Noji · 发表于：Proceedings of the National Academy of Sciences · 年份：2002 · DOI：10.1073/pnas.112212199 · 被引用次数：465 · 研究领域：Congenital limb and hand anomalies、Hedgehog Signaling Pathway Studies、Developmental Biology and Gene Regulation

Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1/Lmbr1 gene, which resides approximately 1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human.