Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Vandervore, Laura; Schot, Rachel; Kasteleijn, Esmee; Oegema, Renske; Stouffs, Katrien; Gheldof, Alexander; Grochowska, Martyna M; Sterre, Marianne L. T. van der; Unen, Leontine van; Wilke, Martina; Elfferich, Peter; Spek, Peter J. van der; Heijsman, Daphne; Grandone, Anna; Demmers, Jeroen; Dekkers, Dick H. W.; Slotman, Johan A.; Kremers, Gert Jan; Schaaf, Gerben; Masius, Roy; Essen, Anton J. Van; Rump, Patrick; Haeringen, Arie van; Peeters, Els; Altunoğlu, Umut; Kalaycı, Tuğba; Poot, Raymond A.; Dobyns, William B.; Bahi‐Buisson, Nadia; Verheijen, Frans W.; Jansen, Anna; Mancini, Grazia M.S.

doi:10.1093/brain/awz045

Cited by 25 publications

(44 citation statements)

References 56 publications

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“…A large number of neurological disease-linked genes regulate signaling pathways affecting myosin function, whereas MYH mutations are associated with intellectual disability, autism, and schizophrenia. NMII also interacts with rotatin, whose mutations cause microcephaly and intellectual disability, and tau, a central protein in AD and frontotemporal dementias [ 149 , 150 ]. The contributions of these mutations to myosin dysfunction in neurological and neuropsychiatric diseases need further confirmation.…”

Section: Discussionmentioning

confidence: 99%

“…A similar phenotype is partially modeled by germline deletion of Myh9 in mice [ 44 ], which suggests that loss of Myh function causes severe developmental cerebral defects. More recent proteomic studies have identified NMIIA, B, and C as binding partners of rotatin ( RTTN ) , the gene of which is mutated in some cerebral pathologies, such as severe intellectual disability, cortical malformation, microcephaly, and polymicrogyria with seizures [ 149 ]. Although the specific mechanisms by which rotatin mutations trigger neurodevelopmental malformations remain unclear, it is tempting to speculate that these defects could be partially mediated by NMII.…”

Section: Non-muscle Myosin II In Neurological and Neurodegenerativmentioning

confidence: 99%

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Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

Javier-Torrent

Saura

2020

Cells

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Myosins are motor proteins that use chemical energy to produce mechanical forces driving actin cytoskeletal dynamics. In the brain, the conventional non-muscle myosin II (NMII) regulates actin filament cytoskeletal assembly and contractile forces during structural remodeling of axons and dendrites, contributing to morphology, polarization, and migration of neurons during brain development. NMII isoforms also participate in neurotransmission and synaptic plasticity by driving actin cytoskeletal dynamics during synaptic vesicle release and retrieval, and formation, maturation, and remodeling of dendritic spines. NMIIs are expressed differentially in cerebral non-neuronal cells, such as microglia, astrocytes, and endothelial cells, wherein they play key functions in inflammation, myelination, and repair. Besides major efforts to understand the physiological functions and regulatory mechanisms of NMIIs in the nervous system, their contributions to brain pathologies are still largely unclear. Nonetheless, genetic mutations or deregulation of NMII and its regulatory effectors are linked to autism, schizophrenia, intellectual disability, and neurodegeneration, indicating non-conventional roles of NMIIs in cellular mechanisms underlying neurodevelopmental and neurodegenerative disorders. Here, we summarize the emerging biological roles of NMIIs in the brain, and discuss how actomyosin signaling contributes to dysfunction of neurons and glial cells in the context of neurological disorders. This knowledge is relevant for a deep understanding of NMIIs on the pathogenesis and therapeutics of neuropsychiatric and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Non-muscle Myosin II In Neurological and Neurodegenerativmentioning

confidence: 99%

Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

Javier-Torrent

Saura

2020

Cells

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“…WES data analysis and filtering of variants were carried out as previously described (Bogershausen et al, 2015). RT‐PCR was performed as described by Vandervore et al (2019).…”

Section: Methodsmentioning

confidence: 99%

Human RAD50 deficiency: Confirmation of a distinctive phenotype

Ragamin

Yiğit

Bousset

et al. 2020

American J of Med Genetics Pt A

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DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks.Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype. K E Y W O R D SDNA repair, microcephaly, MRN complex, Nijmegen breakage syndrome-like disorder, RAD50

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“…The evaluation process include accurate classification based on neuroimaging analysis, detailed family history and a search for gestational insults as possible non-genetic causes of the malformation. Dr. Mancini and her team were able to link monogenetic mutations, chromosomal anomalies and copy number variations to patients presenting various MCDs including microcephaly, lissencephaly, pachygyria, subcortical band heterotopia, cobblestone-type lissencephalies, polymicrogyria (PMG) and schizencephaly (de Wit et al, 2008; Meuwissen et al, 2016; Oegema et al, 2017; Dobyns et al, 2018; Vandervore et al, 2019). In this process, the availability of next generation sequencing tools, open access databases allowing exchange of variants and the multidisciplinary interaction at local and international level have proved great effectiveness.…”

Section: Malformations Of Cortical Development (Mcds): Classificationmentioning

confidence: 99%

Building Bridges Between the Clinic and the Laboratory: A Meeting Review – Brain Malformations: A Roadmap for Future Research

Sapir

Barakat

Paredes

et al. 2019

Front. Cell. Neurosci.

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In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting.

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Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Cited by 25 publications

References 56 publications

Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

Human RAD50 deficiency: Confirmation of a distinctive phenotype

Building Bridges Between the Clinic and the Laboratory: A Meeting Review – Brain Malformations: A Roadmap for Future Research

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