Evidence map›Paper›PMID 39168120›Full record

ArticleAmerican journal of human genetics2024

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

Paranchai Boonsawat, Reza Asadollahi, Dunja Niedrist, Katharina Steindl, Anaïs Begemann, Pascal Joset, Elizabeth J Bhoj, Dong Li, Elaine Zackai, Annalisa Vetro and 21 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors.

Paranchai BoonsawatInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Reza AsadollahiInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland; Faculty of Engineering and Science, University of Greenwich London, Medway Campus, Chatham Maritime ME4 4TB, UK.
Dunja NiedristInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Katharina SteindlInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Anaïs BegemannInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Pascal JosetMedical Genetics, University Hospital Basel, Basel, Switzerland.
Elizabeth J BhojCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Dong LiCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elaine ZackaiDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Annalisa VetroNeuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
Carmen BarbaNeuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy; University of Florence, Florence, Italy.
Renzo GuerriniNeuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
Sandra WhalenUnité Fonctionnelle de Génétique Odellin, Hôpital Armand Trousseau, Paris, France.
Boris KerenDépartement de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France.
Amjad KhanFaculty of Science, Department of Biological Science (Zoology), University of Lakki Marwat, Khyber Pakhtunkhwa 28420, Pakistan.
Duan JingShenzhen Children's Hospital, Shenzhen, Guangdong, China.
María Palomares BraloInstituto de Genética Médica y Molecular (INGEMM), Unidad de Trastornos Del Neurodesarrollo, Hospital Universitario La Paz, Madrid, Spain.
Emi Rikeros OrozcoInstituto de Genética Médica y Molecular (INGEMM), Unidad de Trastornos Del Neurodesarrollo, Hospital Universitario La Paz, Madrid, Spain.
Qin HaoDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Britta Schlott KristiansenDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Bixia ZhengNanjing Key Laboratory of Pediatrics Children's Hospital of Nanjing Medical University, Nanjing, China.
Deirdre DonnellyNorthern Ireland Regional Genetics Centre, Belfast Health & Social Care Trust, Belfast, Northern Ireland.
Virginia ClowesThames Regional Genetics Service, North West University Healthcare NHS Trust, London, UK.
Markus ZweierInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Michael PapikInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Gabriele SiegelInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Valeria SabatinoInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Martina MoceraInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Anselm H C HornInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Heinrich StichtInstitute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Anita RauchInstitute of Medical Genetics, University of Zurich, Zurich, Switzerland; Pediatric University Hospital Zurich, Zurich, Switzerland. Electronic address: anita.rauch@medgen.uzh.ch.

Funding

Wellcome TrustWellcome Trust 098051
6 · The paper itself

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.

Indexed as

BrainGerm-Line MutationNeurodevelopmental DisordersPhenotypeUbiquitin-Protein LigasesWnt Signaling PathwayAdolescentbeta CateninChildChild, PreschoolFemaleGenetic Association StudiesHumansMaleMutation, MissenseProtein Domainsbeta CateninUbiquitin-Protein LigasesZNRF3 protein, humanadrenal insufficiencycongenital heart defectsdominant negativehaploinsufficiencymacrocephalymicrocephalymirror phenotypetumor suppressor geneWnt signalingZNRF3

Identifiers

PMID39168120
PMCPMC11393693

What Socratic holds

Textmetadata
LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.