Mutations in SIX1 Associated with Branchio-oto-Renal Syndrome (BOR) Differentially Affect Otic Expression of Putative Target Genes.
Mutations in SIX1 Associated with Branchio-oto-Renal Syndrome (BOR) Differentially Affect Otic Expression of Putative Target Genes.
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DOI：
10.3390/jdb9030025
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发表时间：
2021-06-30
影响因子：
2.7
通讯作者：
Moody SA
中科院分区：
文献类型：
--
作者：
Mehdizadeh T;Majumdar HD;Ahsan S;Tavares ALP;Moody SA
SIX 1中的几个单核苷酸突变是鳃耳/鳃耳肾（BOR）综合征的基础，但临床文献尚不能将不同的变体与特定的表型相关联。我们先前评估了辅因子结合结构域（V17 E，R110 W）或DNA结合结构域（W122 R，Y129 C）中的变体是否可能差异地影响早期胚胎基因表达，并发现每个变体对神经嵴和基板基因表达具有不同的影响组合。由于耳泡产生内耳，这是一贯影响BOR，在这里我们集中在是否差异影响的基因的耳表达的变异先前发现可能是Six 1的目标。我们发现，不结合Eya辅因子的V17 E在减少大多数耳靶基因方面与野生型Six 1一样有效，而结合Eya的R110 W，W122 R和Y129 C则明显不那么有效。值得注意的是，V17 E减少了耳表达的prdm 1，而R110 W，W122 R和Y129 C扩大它。由于每个突变体有缺陷的转录活性，但在他们的能力不同，相互作用与Eya辅因子，我们建议，改变辅因子的相互作用在突变位点的差异干扰他们的能力，驱动耳基因表达，这些差异可能有助于患者表型变异。
Several single-nucleotide mutations in SIX1 underlie branchio-otic/branchio-oto-renal (BOR) syndrome, but the clinical literature has not been able to correlate different variants with specific phenotypes. We previously assessed whether variants in either the cofactor binding domain (V17E, R110W) or the DNA binding domain (W122R, Y129C) might differentially affect early embryonic gene expression, and found that each variant had a different combination of effects on neural crest and placode gene expression. Since the otic vesicle gives rise to the inner ear, which is consistently affected in BOR, herein we focused on whether the variants differentially affected the otic expression of genes previously found to be likely Six1 targets. We found that V17E, which does not bind Eya cofactors, was as effective as wild-type Six1 in reducing most otic target genes, whereas R110W, W122R and Y129C, which bind Eya, were significantly less effective. Notably, V17E reduced the otic expression of prdm1, whereas R110W, W122R and Y129C expanded it. Since each mutant has defective transcriptional activity but differs in their ability to interact with Eya cofactors, we propose that altered cofactor interactions at the mutated sites differentially interfere with their ability to drive otic gene expression, and these differences may contribute to patient phenotype variability.
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