Kitagawa Michinori
Division of Molecular Neurobiology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Biochem Biophys Res Commun. 2007 Oct 5;361(4):1022-6. doi: 10.1016/j.bbrc.2007.07.129. Epub 2007 Jul 31.
Sveinsson's chorioretinal atrophy (SCRA) is an autosomal dominant eye disease characterized by bilateral chorioretinal degeneration. A missense mutation in the gene encoding the transcription factor TEAD1/TEF-1 (Y421H) is genetically linked to SCRA, but the mechanisms of pathology remain unclear. To study the molecular mechanisms underlying SCRA, a missense mutation corresponding to Y421H in human TEAD1 was introduced into mouse Tead1 (Y410H), and a functional analysis of the mutant protein was performed in RPE-J cells. The missense mutation reduced the ability of Tead1 to interact with the co-factors YAP and TAZ, but not with the co-factors Vgl-1, -2, and -3, in a mammalian two-hybrid assay. A GST pull-down assay showed that the direct interaction between Tead1 and YAP or TAZ was lost owing to the mutation. Amino acid substitutions at position 410 of Tead1 revealed the essentiality of this tyrosine residue to the interaction. The Y410H mutation also abolished the transcriptional activity of Tead1 under the co-expression of YAP or TAZ. These results suggest that SCRA pathogenesis may be due to a loss-of-function of TEAD1 affecting the regulation of its target genes.
斯韦因松脉络膜视网膜萎缩（SCRA）是一种常染色体显性眼病，其特征为双侧脉络膜视网膜变性。编码转录因子TEAD1/TEF-1（Y421H）的基因中的错义突变在遗传上与SCRA相关，但病理机制仍不清楚。为了研究SCRA潜在的分子机制，将人类TEAD1中与Y421H对应的错义突变引入小鼠Tead1（Y410H），并在RPE-J细胞中对突变蛋白进行功能分析。在哺乳动物双杂交试验中，该错义突变降低了Tead1与辅因子YAP和TAZ相互作用的能力，但不影响与辅因子Vgl-1、-2和-3的相互作用。谷胱甘肽-S-转移酶（GST）沉降试验表明，由于该突变，Tead1与YAP或TAZ之间的直接相互作用丧失。Tead1第410位氨基酸的替换揭示了该酪氨酸残基对相互作用的重要性。Y410H突变也消除了在YAP或TAZ共表达情况下Tead1的转录活性。这些结果表明，SCRA的发病机制可能是由于TEAD1功能丧失影响了其靶基因的调控。
