Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling

Boonsawat P, Asadollahi R, Niedrist D, Steindl K, Begemann A, Joset P, Bhoj EJ, Li D, Zackai E, Vetro A, Barba C, Guerrini R, Whalen S, Keren B, Khan A, Jing D, Palomares Bralo M, Rikeros Orozco E, Hao Q, Schlott Kristiansen B, Zheng B, Donnelly D, Clowes V, Zweier M, Papik M, Siegel G, Sabatino V, Mocera M, Horn AH, Sticht H, Rauch A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

American Journal of Human Genetics Elsevier (Cell Press)

DOI: 10.1016/j.ajhg.2024.07.016

Abstract

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants.

Authors with CRIS profile

Heinrich Sticht Professur für Bioinformatik

Involved external institutions

Children's Hospital of Philadelphia US United States (USA) (US) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Meyer Children’s Hospital IT Italy (IT) Hôpital Armand-Trousseau (AP-HP) FR France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) University of Lakki Marwat PK Pakistan (PK) Shenzhen Children's Hospital CN China (CN) Hospital Universitario La Paz ES Spain (ES) Odense Universitetshospital (OUH) DK Denmark (DK) Universitätsspital Basel CH Switzerland (CH) Nanjing Medical University / 南京医科大学 CN China (CN) Belfast Health and Social Care Trust GB United Kingdom (GB) Western University CA Canada (CA)

How to cite

APA:

Boonsawat, P., Asadollahi, R., Niedrist, D., Steindl, K., Begemann, A., Joset, P.,... Rauch, A. (2024). Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2024.07.016

MLA:

Boonsawat, Paranchai, et al. "Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling." American Journal of Human Genetics (2024).

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