Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly
Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly
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DOI：
10.1073/pnas.112212199
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
Noji, S
中科院分区：
文献类型：
--
作者：
Lettice, LA;Horikoshi, T;Noji, S
轴前多指（PPD）是人类常见的肢体畸形。许多多指小鼠突变体表明，Shh的错误表达是产生额外指（趾）的常见必要条件。在此，我们在一名PPD患者中确定了一个易位断点，并在多指小鼠突变体“大脚野人”（Ssq）中确定了一个转基因插入位点。两者的遗传损伤都位于LMBR1/Lmbr1基因的同一内含子内，该基因距离Shh约1 Mb。对Ssq的遗传分析表明，Lmbr1基因与表型无关，该突变直接中断了Shh的一个顺式作用调节因子。这个调节因子很可能是人类产生PPD突变的靶点。
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 approximate to1 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.