Kiefer Susan M, Robbins Lynn, Barina Andrew, Zhang Zhihong, Rauchman Michael
Research and Education Service Line, St. Louis Veterans Administration Medical Center, U.S. Department of Veterans Affairs, St. Louis, Missouri 63106, USA.
Hum Mutat. 2008 Sep;29(9):1133-40. doi: 10.1002/humu.20759.
Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes-Brocks syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense-mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1-DeltaZn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes.
SALL1基因的突变会导致引发汤姆斯-布罗克斯综合征（TBS）的显性多器官先天性异常。这些突变大多会导致提前终止密码子的出现，预计会引发突变mRNA的无义介导衰变（NMD）并导致单倍剂量不足。我们之前使用基因靶向小鼠模型（Sall1-DeltaZn）的研究表明，TBS表型是由于截短的突变蛋白的表达，而非单倍剂量不足。在本报告中，我们通过证明在转基因小鼠中单独表达突变蛋白足以导致具有TBS患者特征的肢体表型，从而强化了这一假设。我们通过证明截短的SALL1蛋白在源自TBS患者的细胞中表达，证实了在小鼠中阐明的相同致病机制也在人类中发生。TBS突变蛋白具有显性负性活性，可导致发育中的心脏和肢体中的两个下游基因Nppa和Shox2异位激活。我们提出了一种TBS发病机制模型，其中截短的Sall1蛋白会导致Sall反应性靶基因的去抑制。
