Mutations in the β-tubulin TUBB impair ciliogenesis and are associated with ciliopathy-like phenotypes

Antonio Mollica, Safia Omer, Georgiana Forguson, Sydney Steiman, Sonia L. Evagelou, Serhiy Naumenko, Susan Walker, Lu Yi Li, Aideen Teeling, Kyle Lindsay, Steven Erwood, Shagana Visuvanathan, Anjali Vig, Robert M. Vernon, Benjamin Akman, Constance Smith-Hicks, Julie D. Forman-Kay, Manohar Shroff, Vivek Pai, Rene E. Harrison, Ronald D. Cohn and Evgueni A. Ivakine ()
Additional contact information
Antonio Mollica: The Hospital for Sick Children, Genetics and Genome Biology Program
Safia Omer: University of Toronto Scarborough, Department of Biological Sciences
Georgiana Forguson: The Hospital for Sick Children, Genetics and Genome Biology Program
Sydney Steiman: The Hospital for Sick Children, Genetics and Genome Biology Program
Sonia L. Evagelou: The Hospital for Sick Children, Genetics and Genome Biology Program
Serhiy Naumenko: Harvard Chan School of Public Health, Department of Biostatistics
Susan Walker: The Hospital for Sick Children, The Centre for Applied Genomics
Lu Yi Li: The Hospital for Sick Children, Genetics and Genome Biology Program
Aideen Teeling: The Hospital for Sick Children, Genetics and Genome Biology Program
Kyle Lindsay: The Hospital for Sick Children, Genetics and Genome Biology Program
Steven Erwood: The Hospital for Sick Children, Genetics and Genome Biology Program
Shagana Visuvanathan: The Hospital for Sick Children, Genetics and Genome Biology Program
Anjali Vig: The Hospital for Sick Children, Genetics and Genome Biology Program
Robert M. Vernon: The Hospital for Sick Children, Molecular Medicine Program
Benjamin Akman: Kennedy Krieger Institute, Department of Neurology and Developmental Medicine
Constance Smith-Hicks: Kennedy Krieger Institute, Department of Neurology and Developmental Medicine
Julie D. Forman-Kay: University of Toronto, Department of Biochemistry
Manohar Shroff: The Hospital for Sick Children, Division of Neuroradiology, Department of Diagnostic and Interventional Radiology
Vivek Pai: The Hospital for Sick Children, Division of Neuroradiology, Department of Diagnostic and Interventional Radiology
Rene E. Harrison: University of Toronto Scarborough, Department of Biological Sciences
Ronald D. Cohn: The Hospital for Sick Children, Genetics and Genome Biology Program
Evgueni A. Ivakine: The Hospital for Sick Children, Genetics and Genome Biology Program

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract Tubulinopathies and neurodevelopmental ciliopathies are two groups of genetic disorders that cause structural brain malformations. Tubulinopathies result from mutations in tubulins, the building blocks of microtubules, most of which are dominant. Neurodevelopmental ciliopathies are mostly recessive disorders caused by defects in the primary cilium, an organelle that regulates key signaling pathways during brain development. Although more than 40 genes have been associated with neurodevelopmental ciliopathies, many patients still lack a known genetic cause. Here, we present a de novo heterozygous missense variant (p.G308S) in Tubulin Beta Class I (TUBB) identified in a patient showing features of both ciliopathy and tubulinopathy. While microtubules are essential for primary cilia formation and function, an association between tubulin mutations and neurodevelopmental ciliopathies has not been established. Using patient-derived cells and gene-edited isogenic cell lines, we show that the identified variant impairs the early stages of cilia formation by altering microtubule dynamics and structure. Consistent with this, mice carrying the variant display decreased ciliation in the cerebellum and kidney. Furthermore, we demonstrate that the disease mechanism is not haploinsufficiency and that other patient mutations in TUBB affect cilia formation, putting forward defective ciliogenesis as a contributing pathogenic factor in a subset of tubulinopathy patients.

Date: 2025
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DOI: 10.1038/s41467-025-65634-x

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