High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency
High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency
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DOI：
10.1016/j.ajhg.2021.06.013
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发表时间：
2021-08-05
影响因子：
9.8
通讯作者：
Camper, Sally A.
中科院分区：
文献类型：
--
作者：
Gergics, Peter;Smith, Cathy;Camper, Sally A.
孕激素缺乏症的发生率与1：4，000活产婴儿相似。大约3%的病例是由于POU1F1（一种垂体特异性转录激活因子）的α亚型突变所致。我们发现四个独立的杂合错义变异体无关的个体垂体功能减退，预计影响一个较小的亚型，POU1F1 β，它可以作为转录抑制因子。这些变体保留阻遏物活性，但它们改变剪接以有利于β同种型的表达，导致显性阴性功能丧失。使用高通量剪接报告分析，我们测试了POU1F1中的1，070个单核苷酸变体。我们确定了96个剪接破坏性变异，包括14个同义变异。在单独的队列中，我们发现了两个额外的同义变异提名的这个屏幕，共分离与垂体功能减退。这项研究强调了评估变异对剪接的影响的重要性，并提供了一个解释POU1F1中未知意义的变异的目录。
Pituitary hormone deficiency occurs in similar to 1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.