Holoprosencephaly (HPE) is the most common congenital anomaly affecting the forebrain and face in humans and occurs as frequently as 1:250 conceptions or 1:10,000 livebirths. Sonic Hedgehog signaling molecule is one of the best characterized HPE genes that plays crucial roles in numerous developmental processes including midline neural patterning and craniofacial development. The Frizzled class G‐protein coupled receptor Smoothened (SMO), whose signaling activity is tightly regulated, is the sole obligate transducer of Hedgehog‐related signals. However, except for previous reports of somatic oncogenic driver mutations in human cancers (or mosaic tumors in rare syndromes), any potential disease‐related role of SMO genetic variation in humans is largely unknown. To our knowledge, ours is the first report of a human hypomorphic variant revealed by functional testing of seven distinct nonsynonymous SMO variants derived from HPE molecular and clinical data. Here we describe several zebrafish bioassays developed and guided by a systems biology analysis. This analysis strategy, and detection of hypomorphic variation in human SMO, demonstrates the necessity of integrating the genomic variant findings in HPE probands with other components of the Hedgehog gene regulatory network in overall medical interpretations.

中文翻译：

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SMO 的七螺旋域中罕见的亚形人类变异有助于全前脑表型。

前脑畸形 (HPE) 是影响人类前脑和面部的最常见先天性异常，发生频率高达 1:250 受孕或 1:10,000 活产。Sonic Hedgehog 信号分子是表征最好的 HPE 基因之一，在许多发育过程中起着至关重要的作用，包括中线神经模式和颅面发育。Frizzled 类 G 蛋白偶联受体Smoothened ( SMO )，其信号活动受到严格调控，是 Hedgehog 相关信号的唯一专性转导器。然而，除了先前关于人类癌症（或罕见综合征中的镶嵌肿瘤）中体细胞致癌驱动突变的报告外，SMO 的任何潜在疾病相关作用人类的遗传变异在很大程度上是未知的。据我们所知，我们的报告是通过对源自 HPE 分子和临床数据的七个不同非同义SMO变体的功能测试揭示的人类亚形变体的第一份报告。在这里，我们描述了由系统生物学分析开发和指导的几种斑马鱼生物测定。这种分析策略和人类SMO 亚形变异的检测表明，在整体医学解释中，有必要将 HPE 先证者的基因组变异发现与 Hedgehog 基因调控网络的其他成分相结合。