MD Undergraduate Program, University of British Columbia, Vancouver, British Columbia, Canada.
Provincial Medical Genetics Program, B.C. Women's Hospital, Vancouver, British Columbia, Canada.
Am J Med Genet A. 2023 Jun;191(6):1593-1598. doi: 10.1002/ajmg.a.63167. Epub 2023 Mar 3.
The Notch proteins play key roles in cell fate determination during development. Germline pathogenic variants in NOTCH1 predispose to a spectrum of cardiovascular malformations including Adams-Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C-terminus of the single-pass transmembrane receptor encoded by NOTCH1 contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a NOTCH1-mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss-of-function protein that acts as an antimorph through competition with wild-type NOTCH1.
Notch 蛋白在发育过程中细胞命运决定中发挥关键作用。NOTCH1 种系致病性变异易导致多种心血管畸形，包括 Adams-Oliver 综合征和广泛的各种孤立的复杂和简单的先天性心脏缺陷。NOTCH1 编码的单次跨膜受体的细胞内 C 末端包含一个转录激活结构域（TAD），对于靶基因激活是必需的，以及一个 PEST 结构域（富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的序列），调节蛋白质稳定性和周转率。我们提出了一例新的变异，该变异编码一种截断的 NOTCH1 蛋白，没有 TAD 和 PEST 结构域（NM_017617.4：c.[6626_6629del]；[=]，p.（Tyr2209CysfsTer38）），并伴有广泛的心血管异常，符合 NOTCH1 介导的机制。通过荧光素酶报告基因分析评估，该变异不能促进靶基因的转录。鉴于 TAD 和 PEST 结构域在 NOTCH1 功能和调节中的作用，我们假设 TAD 和 PEST 结构域的缺失均导致稳定的、功能丧失的蛋白，通过与野生型 NOTCH1 竞争作为抗形发挥作用。
