Fujiwara Takayuki, Takeda Norifumi, Ishii Satoshi, Morita Hiroyuki, Komuro Issei
Department of Cardiovascular Medicine, The University of Tokyo Hospital Tokyo Japan.
Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo Tokyo Japan.
Circ Rep. 2019 Nov 2;1(11):487-492. doi: 10.1253/circrep.CR-19-0098.
Variant types and sites in a single gene could influence the age of onset, severity, and pattern of affected organs of the genetic disease, such as in Marfan syndrome (MFS)-causing , and understanding the genotype-phenotype relationship could aid in determining the treatment strategy. In contrast, completely distinct system and/or organ diseases induced by 1 gene mutation have been rarely reported. Transforming growth factor-β (TGF-β) type I receptor-encoding is such a gene, causing Loeys-Dietz syndrome (LDS) closely related to MFS, and also multiple self-healing squamous epithelioma (MSSE) without clinical overlap. The detailed mechanisms underlying this effect, however, remain elusive. We recently reported the significance of 2 distinct intronic variants (c.973+1G>A and c.806-2A>C) of , which were both predicted to mediate in-frame exon 5 skipping but caused LDS and MSSE, respectively. On ex vivo minigene splicing assay analysis we demonstrated that 2 different cryptic splice sites were activated, and in-frame and out-of-frame transcripts were produced in LDS and MSSE, respectively, supporting the previously proposed but not yet approved mechanism that loss-of-function and haploinsufficiency-causing variants in serine/threonine kinase domains induce LDS and MSSE, respectively. In this review, we briefly summarize the recent findings and unresolved problems for the pathogenesis of LDS, including the TGF-β signaling paradox: most variants have been verified or predicted to be loss of function in vitro, but these variants enhanced TGF-β signaling in vivo.
单个基因中的变异类型和位点可能会影响遗传疾病的发病年龄、严重程度和受累器官模式，如在导致马凡综合征（MFS）的基因中，了解基因型与表型的关系有助于确定治疗策略。相比之下，由单个基因突变引发的完全不同的系统和/或器官疾病鲜有报道。编码转化生长因子-β（TGF-β）I型受体的基因就是这样一个例子，它会导致与MFS密切相关的洛伊迪茨综合征（LDS），还会引发无临床重叠的多发性自愈性鳞状上皮瘤（MSSE）。然而，这种效应背后的详细机制仍不清楚。我们最近报道了该基因两个不同内含子变异（c.973+1G>A和c.806-2A>C）的重要性，这两个变异均被预测介导框内第5外显子跳跃，但分别导致了LDS和MSSE。在体外小基因剪接分析中，我们证明激活了两个不同的隐蔽剪接位点，LDS和MSSE分别产生了框内和框外转录本，支持了先前提出但尚未得到证实的机制，即丝氨酸/苏氨酸激酶结构域中导致功能丧失和单倍剂量不足的变异分别诱发LDS和MSSE。在这篇综述中，我们简要总结了LDS发病机制的最新研究发现和未解决的问题，包括TGF-β信号悖论：大多数变异在体外已被证实或预测为功能丧失，但这些变异在体内却增强了TGF-β信号。
