HNRNPU: Key to Neurodevelopmental Disorders such as Intellectual Delay, Epilepsy, and Autism

Poot, Martin

doi:10.1159/000495204

Cited by 7 publications

(5 citation statements)

References 36 publications

(50 reference statements)

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“…Microdeletions in the 1q44 locus encompassing HNRNPU and other genes, as well as point mutations in HNRNPU, result in brain disorders, including early-onset seizures, severe intellectual disability, and lower penetrance microcephaly, a thin corpus callosum, dysmorphic facial features, and hypotonia [15][16][17][18][19][20][21] (reviewed by ref. 22 ). However, understanding of HNRNPU's functions in the developing brain is lacking.…”

mentioning

confidence: 99%

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex

et al. 2022

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HNRNPU encodes the heterogeneous nuclear ribonucleoprotein U, which participates in RNA splicing and chromatin organization. Microdeletions in the 1q44 locus encompassing HNRNPU and other genes and point mutations in HNRNPU cause brain disorders, including early-onset seizures and severe intellectual disability. We aimed to understand HNRNPU’s roles in the developing brain. Our work revealed that HNRNPU loss of function leads to rapid cell death of both postmitotic neurons and neural progenitors, with an apparent higher sensitivity of the latter. Further, expression and alternative splicing of multiple genes involved in cell survival, cell motility, and synapse formation are affected following Hnrnpu’s conditional truncation. Finally, we identified pharmaceutical and genetic agents that can partially reverse the loss of cortical structures in Hnrnpu mutated embryonic brains, ameliorate radial neuronal migration defects and rescue cultured neural progenitors’ cell death.

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confidence: 99%

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex

et al. 2022

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“…Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with ID, also displaying seizures, microcephaly, and corpus callosum abnormalities. HNRNPU, a key player in brain development [Poot, 2019], is considered as the major determinant of epilepsy in these patients [Depienne et al, 2017].…”

Section: Resultsmentioning

confidence: 99%

“…The HNRNPU protein is located in the nucleus and binds to its matrix, helping localize genes and proteins (including transcription factors within the nucleus) and facilitates gene, mRNA, and protein interactions during mRNA processing, thus regulating gene expression [Leduc et al, 2017;Poot, 2019].…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Treatment of Severe Breathing Abnormalities in a Case of HNRNPU Epileptic Encephalopathy

et al. 2021

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Abnormal breathing patterns are a typical feature of Rett and Pitt-Hopkins syndrome and their variants. Their treatment can be challenging, with a risk of long-term detrimental consequences. Early infantile epileptic encephalopathy (EIEE) type 54 is a rare epileptic encephalopathy caused by pathogenic variants in the heterogeneous nuclear ribonucleoprotein U (HNRNPU) gene. Only one case has been described in the literature with episodes of hyperventilation and apnea, but treatment was not discussed. We describe the clinical and genetic features and treatment strategies in a case of EIEE type 54 and severely abnormal breathing pattern. A novel and likely pathogenic c.2277dup, p.(Pro760Serfs*5) variant in the HNRNPU gene was found in a male patient with severe episodes of hyperventilation and apnea, leading to syncope. Combination therapy with acetazolamide, alprazolam and aripiprazole led to significant clinical improvement. Although HNRNPU has not been implicated in breathing control, pathogenic variants in this gene can be associated with the development of abnormal breathing patterns reminiscent of Rett and Pitt-Hopkins syndrome. Its function as a gene expression regulator and its interaction with transcription factors offers a potential pathogenetic link between these 3 disorders. Based on our experience, treatment strategies can be similar to those already applied for patients with Pitt-Hopkins and Rett syndrome.

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“…SAFA is a multimodular protein involved in the structural organization of nuclear matrix ( 42 ), genome integrity ( 84 ), transcription regulation ( 8 ), alternative splicing ( 3 ), and mRNA stability ( 11 ). Alterations in SAFA levels and function are linked to numerous diseases, including cancer and to cardiovascular, neurological, and developmental disorders ( 4 , 17 , 18 , 20 , 85 ). Recent reports suggest that SAFA plays an instrumental role in cell fate decisions by regulating gene expression of coding and non-coding genes ( 14 , 86 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Cell-Penetrating Peptides Derived From Scaffold-Attachment- Factor A Inhibits Cancer Cell Proliferation and Survival

Puvvula

Moon

2021

Front. Oncol.

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Scaffold-attachment-factor A (SAFA) has important roles in many normal and pathologic cellular processes but the scope of its function in cancer cells is unknown. Here, we report dominant-negative activity of novel peptides derived from the SAP and RGG-domains of SAFA and their effects on proliferation, survival and the epigenetic landscape in a range of cancer cell types. The RGG-derived peptide dysregulates SAFA binding and regulation of alternatively spliced targets and decreases levels of key spliceosome proteins in a cell-type specific manner. In contrast, the SAP-derived peptide reduces active histone marks, promotes chromatin compaction, and activates the DNA damage response and cell death in a subset of cancer cell types. Our findings reveal an unprecedented function of SAFA-derived peptides in regulating diverse SAFA molecular functions as a tumor suppressive mechanism and demonstrate the potential therapeutic utility of SAFA-peptides in a wide range of cancer cells.

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HNRNPU: Key to Neurodevelopmental Disorders such as Intellectual Delay, Epilepsy, and Autism

Cited by 7 publications

References 36 publications

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex

Pharmacological Treatment of Severe Breathing Abnormalities in a Case of HNRNPU Epileptic Encephalopathy

Novel Cell-Penetrating Peptides Derived From Scaffold-Attachment- Factor A Inhibits Cancer Cell Proliferation and Survival

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