Pathogenic variants in nucleoporin <i>TPR (translocated promoter region, nuclear basket protein)</i> cause severe intellectual disability in humans

Bergen, Nicole J Van; Bell, Katrina M.; Carey, Kirstyn T.; Gear, Russell; Massey, Sean; Murrell, Edward K; Gallacher, Lyndon; Pope, Kate; Lockhart, Paul J.; Kornberg, Andrew J.; Pais, Lynn; Walkiewicz, Marzena; Simons, Cas; Wickramasinghe, Vihandha O.; White, Susan; Christodoulou, John

doi:10.1093/hmg/ddab248

Cited by 8 publications

(5 citation statements)

References 62 publications

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“…3a, suggesting nuclei with more nuclear pore complexes (NPCs) experience more transport. The only exception was TPR, which has been reported to negatively regulate NPC assembly, as validated through knockdowns of TPR yielding cells with more assembled NPCs 49 , as well as in patient fibroblasts with reduced TPR abundances 52 . Interestingly, our data support these previous results, as TPR is the only nucleoporin whose abundance was negatively associated with protein transport.…”

Section: More Nuclear Pore Complexes More Transportmentioning

confidence: 96%

Single-nucleus proteomics identifies regulators of protein transport

Derks,

Jonson,

Leduc

et al. 2024

Preprint

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The physiological response of a cell to stimulation depends on its proteome configuration. Therefore, the abundance variation of regulatory proteins across unstimulated single cells can be associatively linked with their response to stimulation. Here we developed an approach that leverages this association across individual cells and nuclei to systematically identify potential regulators of biological processes, followed by targeted validation. Specifically, we applied this approach to identify regulators of nucleocytoplasmic protein transport in macrophages stimulated with lipopolysaccharide (LPS). To this end, we quantified the proteomes of 3,412 individual nuclei, sampling the dynamic response to LPS treatment, and linking functional variability to proteomic variability. Minutes after the stimulation, the protein transport in individual nuclei correlated strongly with the abundance of known protein transport regulators, thus revealing the impact of natural protein variability on functional cellular response. We found that simple biophysical constraints, such as the quantity of nuclear pores, partially explain the variability in LPS-induced nucleocytoplasmic transport. Among the many proteins newly identified to be associated with the response, we selected 16 for targeted validation by knockdown. The knockdown phenotypes confirmed the inferences derived from natural protein and functional variation of single nuclei, thus demonstrating the potential of (sub-)single-cell proteomics to infer functional regulation. We expect this approach to generalize to broad applications and enhance the functional interpretability of single-cell omics data.

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Section: More Nuclear Pore Complexes More Transportmentioning

confidence: 96%

Single-nucleus proteomics identifies regulators of protein transport

Derks,

Jonson,

Leduc

et al. 2024

Preprint

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“…Within the nuclear basket, aside from the recently identified ALS-linked Nup50 variants, TPR mutations can lead to microcephaly, ataxia, and intellectual disabilities [ 258 ]. In patient cells, these TPR mutations lead to decreased protein levels, reducing the amount of nuclear mRNA and increasing the number of NPCs per nucleus [ 258 ].…”

Section: Nucleoporin Variation and Diseasementioning

confidence: 99%

Nuclear pore dysfunction and disease: a complex opportunity

Fare,

Rothstein

2024

Nucleus

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The separation of genetic material from bulk cytoplasm has enabled the evolution of increasingly complex organisms, allowing for the development of sophisticated forms of life. However, this complexity has created new categories of dysfunction, including those related to the movement of material between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions to nuclear integrity and nucleocytoplasmic transport are detrimental to cell survival. This is particularly true in post-mitotic neurons, where nuclear pore injury and errors to nucleocytoplasmic trafficking are strongly associated with neurodegenerative disease. In this review, we summarize the current understanding of nuclear pore biology in physiological and pathological contexts and discuss potential therapeutic approaches for addressing nuclear pore injury and dysfunctional nucleocytoplasmic transport.

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“…This indicates that NUA functions not only in mRNA export, but also sumoylation [ 84 ]. In human, biallelic variants in TPR (NUA in plants) cause microcephaly, ataxia and severe intellectual disability, accompanied by a decrease in nucleus global RNA intensity [ 85 ]. This cognition regarding the nuclear basket shows that beyond providing anchors for mRNA transport, it has another mechanism involved in regulating transcription.…”

Section: Defensive Roles Of Npc In Plantsmentioning

confidence: 99%

Function of Nuclear Pore Complexes in Regulation of Plant Defense Signaling

Wang

Han

Guo

2022

IJMS

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In eukaryotes, the nucleus is the regulatory center of cytogenetics and metabolism, and it is critical for fundamental biological processes, including DNA replication and transcription, protein synthesis, and biological macromolecule transportation. The eukaryotic nucleus is surrounded by a lipid bilayer called the nuclear envelope (NE), which creates a microenvironment for sophisticated cellular processes. The NE is perforated by the nuclear pore complex (NPC), which is the channel for biological macromolecule bi-directional transport between the nucleus and cytoplasm. It is well known that NPC is the spatial designer of the genome and the manager of genomic function. Moreover, the NPC is considered to be a platform for the continual adaptation and evolution of eukaryotes. So far, a number of nucleoporins required for plant-defense processes have been identified. Here, we first provide an overview of NPC organization in plants, and then discuss recent findings in the plant NPC to elaborate on and dissect the distinct defensive functions of different NPC subcomponents in plant immune defense, growth and development, hormone signaling, and temperature response. Nucleoporins located in different components of NPC have their unique functions, and the link between the NPC and nucleocytoplasmic trafficking promotes crosstalk of different defense signals in plants. It is necessary to explore appropriate components of the NPC as potential targets for the breeding of high-quality and broad spectrum resistance crop varieties.

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Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans

Cited by 8 publications

References 62 publications

Single-nucleus proteomics identifies regulators of protein transport

Single-nucleus proteomics identifies regulators of protein transport

Nuclear pore dysfunction and disease: a complex opportunity

Function of Nuclear Pore Complexes in Regulation of Plant Defense Signaling

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