A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

Fertuzinhos, Sofia; Legué, Emilie; Li, Davis; Liem, Karel F.

doi:10.1126/sciadv.abf7262

Cited by 12 publications

(12 citation statements)

References 63 publications

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“…In mouse ependymal cells, for example, which express high levels of Tubb4b and show a tubulin isotype expression pattern similar to ciliated airway cells (Extended data-Fig 3o), centriole amplification and ciliogenesis are nevertheless grossly normal in the absence of TUBB4B. This observation suggests that other isotypes may compensate for the loss of TUBB4B function, including the highly similar TUBB4A (38). These observations are consistent with Drosophila studies suggesting that only isotypes with a particular amino acid sequence in the carboxyl terminus (EGEFXXX) are required for normal axonemal function (1,6,39,40).…”

Section: Discussionmentioning

confidence: 90%

TUBB4Bvariants specifically impact ciliary function, causing a ciliopathic spectrum

Mechaussier

Dodd

Yeyati

et al. 2022

Preprint

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Cilia are small microtubule-based structures found on the surface of most mammalian cells, which have key sensory and sometimes motile functions. Primary ciliary dyskinesia (PCD) is a type of ciliopathy caused by defects in motile cilia. The genetic basis of PCD is only partially understood. Studying a cohort of 11 human patients with PCD, we find thatde novomutations inTUBB4B, a beta tubulin isotype, cause three distinct classes of ciliopathic disease.In vivostudies in mice show thatTubb4bplays a specific role in cilia, building centrioles and axonemes in multiciliated cells. Examining the effects of specific TUBB4B variants in cells and in mice, we further demonstrate that distinctTUBB4Bmutations differentially affect microtubule dynamics and cilia formation in a dominant negative manner. Finally, structure-function studies reveal that different TUBB4B mutations disrupt distinct tubulin interfaces. Importantly, these molecular differences correlate with disease features. We show that tubulin heterodimer-impairing TUBB4B variants underlie nonsyndromic PCD, whilst additional renal and sensorineural ciliopathic features in a syndromic PCD subtype arise from microtubule lumenal interface-impaired TUBB4B variants. These findings suggest that specific tubulin isotypes have distinct and non-redundant subcellular functions, and demonstrate that human tubulinopathies can be drivers of ciliopathic syndromes.

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Section: Discussionmentioning

confidence: 90%

TUBB4Bvariants specifically impact ciliary function, causing a ciliopathic spectrum

Mechaussier

Dodd

Yeyati

et al. 2022

Preprint

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“…We next analyzed a Tubb4b knockout to test the role of Tubb4b in cilia, because we previously reported that the Tubb4a knockout mouse was non-phenotypic ( Fertuzinhos et al, 2022 ). We generated Tubb4b knockout mice from EUCOMM embryonic stem (ES) cells, in which the middle two of the four exons in Tubb4b are deleted, resulting in an allele that is likely null and not transcribed, as shown by RT-PCR ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Tubb4b is required for multi-ciliogenesis in the mouse

Sewell,

Legué,

Liem

2024

Development

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Cilia are microtubule (MT)-based organelles present on the surface of nearly all vertebrate cells. MTs are polymers of alpha and beta tubulins that are each encoded by multiple, individual isotype genes. Tubulin isotype composition is thought to influence MT behaviors. Ciliary MTs differ from other MTs in the cell in terms of organization, stability and post-translational modifications. However, little is known about the tubulin isotypes that build ciliary MTs and the functional requirements for tubulin isotypes in cilia have not been examined in vertebrates. Here we tested the role of the beta tubulin isotype genes in the mouse that harbor a conserved amino acid motif associated with ciliated organisms. We found that Tubb4b localizes to cilia in multi-ciliated cells (MCC) specifically. In respiratory and oviduct MCC, Tubb4b is asymmetrically localized within multi-cilia, indicating that the tubulin isotype composition changes along the length of the ciliary axonemal MTs. Deletion of Tubb4b resulted in striking structural defects within the axonemes of multi-cilia without affecting primary cilia. These studies show that Tubb4b is essential for the formation of a specific MT-based subcellular organelle and sheds light on the requirements of tubulin isotypes in cilia.

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“…Particularly, 6 of the 23 paralogs of TUBB (Tubulin beta class I) may have been upregulated after TUBB mutation (Figure S1D). Intriguingly, others have experimentally shown that mutations of tubulins can lead to tubulin paralog upregulation in a mouse model of neurodegeneration 29 .…”

Section: Resultsmentioning

confidence: 99%

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Mellis

Bodkin²,

Goyal³

2023

Preprint

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Cells and tissues have a remarkable ability to adapt to genetic perturbations via a variety of molecular mechanisms. Nonsense-induced transcriptional compensation, a form of transcriptional adaptation, has recently emerged as one such mechanism, in which nonsense mutations in a gene can trigger upregulation of related genes, possibly conferring robustness at cellular and organismal levels. However, beyond a handful of developmental contexts and curated sets of genes, to date, no comprehensive genome-wide investigation of this behavior has been undertaken for mammalian cell types and contexts. Moreover, how the regulatory-level effects of inherently stochastic compensatory gene networks contribute to phenotypic penetrance in single cells remains unclear. Here we combine computational analysis of existing datasets with stochastic mathematical modeling and machine learning to uncover the widespread prevalence of transcriptional adaptation in mammalian systems and the diverse single-cell manifestations of minimal compensatory gene networks. Regulon gene expression analysis of a pooled single-cell genetic perturbation dataset recapitulates our model predictions. Our integrative approach uncovers several putative hits-genes demonstrating possible transcriptional adaptation-to follow up on experimentally, and provides a formal quantitative framework to test and refine models of transcriptional adaptation.

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A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy

Cited by 12 publications

References 63 publications

TUBB4Bvariants specifically impact ciliary function, causing a ciliopathic spectrum

TUBB4Bvariants specifically impact ciliary function, causing a ciliopathic spectrum

Tubb4b is required for multi-ciliogenesis in the mouse

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

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