NOTCH1 loss of the TAD and PEST domain: An antimorph?

• Published in: American journal of medical genetics. Part A 2023-06, Vol.191 (6), p.1593-1598
• Main Authors: Boerkoel, Pierre, Huynh, Stephanie, Yang, Gui Xiang, Boerkoel, Cornelius F., Patel, Millan S., Lehman, Anna, Terry, Jefferson, Elbert, Adrienne
• Format: Article
• Language: English
• Subjects: Adams‐Oliver syndrome; Cell fate; Cell surface receptors; Ectodermal Dysplasia - genetics; Glutamic acid; Humans; Limb Deformities, Congenital - genetics; Notch1; Notch1 protein; Notch‐signaling; Pests; Protein turnover; Proteins; Receptor, Notch1 - genetics; Scalp Dermatoses - congenital; Threonine; vascular malformation
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.63167

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.