Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome

Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.

Authors

Institutions

Publication Details

Journal
EMBO Molecular Medicine
Published
2024-11-28
DOI
https://doi.org/10.1038/s44321-024-00178-z
Citations
1
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
0.23

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome

Peggy Tilly, Sateesh Maddirevula, Stephan C. Collins, Efil Bayam et al.
1 citations
EMBO Molecular Medicine
RNA modifications and cancer
0.23
article

Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome

Peggy Tilly, Sateesh Maddirevula, Stephan C. Collins, Efil Bayam, Mustafa A. Salih, Noémie Schwaller, Meghna Kannan, Binnaz Yalcin, Elena Brivio, Carlos M. Guardia, M Stabile, Mitsuhiro Kato, Paolo Giacobini, José Rivera Alvarez, Fernando Kok, Zafer Yüksel, Saeed Al Tala, Bruno Rinaldi, Juliette D. Godin, Fabíola Paoli Monteiro, Mitsuko Nakashima, Ludovica Cotellessa, Hirotomo Saitsu, Fowzan Sami Alkuraya, Sylvie Friant, Lucile Tonneau, Romain Lecat, João Paulo Kitajima, Hiroko Tada, Ahlam A. Hamed, Mais Hashem
article en
1 citations

Abstract

Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.

EMBO Molecular MedicineVol. 17(1)
SHOWA Medical University (JP), King Abdulaziz City for Science and Technology (SA), Centre National de la Recherche Scientifique (FR), University of Salerno (IT), Alfaisal University (SA), University of Khartoum (SD), Inserm (FR), Université de Bourgogne (FR), Universidade de São Paulo (BR), Université de Lille (FR), King Faisal Specialist Hospital & Research Centre (SA), Centre Hospitalier Universitaire de Lille (FR), Hamamatsu University School of Medicine (JP), Chibaken Saiseikai Narashino Hospital (JP), Institut de génétique et de biologie moléculaire et cellulaire (FR), Centre National pour la Recherche Scientifique et Technique (CNRST) (MA), National Institute of Environmental Health Sciences (US), Centre de Recherche Jean Pierre Aubert (FR), Tokyo Metropolitan Institute of Medical Science (JP), Armed Forces Hospital (SA), Mendelics (BR), Université de Strasbourg (FR)
Takeda Science Foundation, Japan Agency for Medical Research and Development, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation Fyssen, Université de Strasbourg, Centre National de la Recherche Scientifique, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Japan Society for the Promotion of Science, National Institute of Environmental Health Sciences
Openalex Percentile: Top 41%
RNA modifications and cancer
0.23
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.