Development & Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney 2010, Australia.
Faculty of Medicine, UNSW, Sydney 2052, Australia.
Hum Mol Genet. 2020 Dec 4;29(22):3662-3678. doi: 10.1093/hmg/ddaa258.
The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.
多种先天性畸形的遗传原因尚不完全清楚。在这里，我们报道了七个无关家系中 WW 结构域结合蛋白 11（WBP11）基因中新型杂合预测失活（LoF）和预测有害错义变异，这些家系具有多种重叠的先天性畸形，包括心脏、椎体、气管食管、肾脏和肢体缺陷。WBP11 编码剪接体的一个组成部分，具有激活前信使 RNA 剪接的能力。我们使用 CRISPR-Cas9 靶向技术在小鼠中生成了一个 Wbp11 缺失等位基因。Wbp11 纯合缺失胚胎在 E8.5 之前死亡，表明 Wbp11 对发育至关重要。由于胚胎和产后死亡，发现的 Wbp11 杂合缺失小鼠比预期的要少。重要的是，Wbp11 杂合缺失小鼠体型较小，并且存在轴骨骼、肾脏和食管缺陷，与受影响的个体相似，这支持了 WBP11 杂合不足在人类先天性畸形发育中的作用。LoF WBP11 变体应被视为 VACTERL 关联以及孤立的 Klippel-Feil 综合征、肾发育不全或食管闭锁的可能原因。
