Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Jeanne, Médéric; Demory, Hélène; Moutal, Aubin; Vuillaume, Marie‐Laure; Blesson, Sophie; Thépault, Rose Anne; Marouillat, Sylviane; Halewa, Judith; Maas, Saskia M.; Motazacker, Mahdi M.; Mancini, Grazia M.S.; Slegtenhorst, Marjon A. van; Andreou, Avgi; Cox, Helene; Vogt, Julie; Laufman, Jason; Kostandyan, Natella; Babikyan, Davit; Hančárová, Miroslava; Bendová, Šárka; Sedláček, Zdeněk; Aldinger, Kimberly A.; Sherr, Elliott H.; Argilli, Emanuela; England, Eleina; Audebert‐Bellanger, Séverine; Bonneau, Dominique; Colin, Estelle; Denommé‐Pichon, Anne‐Sophie; Gilbert‐Dussardier, Brigitte; Isidor, Bertrand; Küry, Sébastien; Odent, Sylvie; Redon, Richard; Khanna, Rajesh; Dobyns, William B.; Bézieau, Stéphane; Honnorat, Jérôme; Lohkamp, Bernhard; Toutain, Annick; Laumonnier, Frédéric

doi:10.1016/j.ajhg.2021.04.004

Cited by 26 publications

(24 citation statements)

References 35 publications

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“…However, our analyses indicate a much stronger enrichment for the cortico-striatum circuitries (Figure 2D - E). DPYSL5 belongs to the collapsin response mediator protein (CRMP) family, and was implicated specifically with axonal growth by converging evidence from case studies 32 , molecular mapping 33 , and animal studies 34 . Interestingly, all CRMP family proteins shows association signals more evidently with ND ( Dpysl2 , p = 1.3e-14; Dpysl3 , p = 9e-7; Dpysl4 , p = 5e-8).…”

Section: Resultsmentioning

confidence: 99%

“…Instead of cortical surface, our whole-brain multivariate GWAS indicates the effect sizes were more diffusely distributed among white matter tracts, especially within cortico-striatal circuitry (Figure 3g, 3h, Supplementary Table 7). DPYSL5 belongs to the collapsin response mediator protein (CRMP) family, including DPYSL2 , DPYSL3 , and DPYSL4 , which are essential for axonal growth and neurite morphogenesis 47–49 (Figure 3i). Indeed, all tagged SNPs of the CRMP family proteins show stronger association signals with ND than with N0 and NF (Figure 3j).…”

Section: Resultsmentioning

confidence: 99%

“…DPYSL5 belongs to the collapsin response mediator protein (CRMP) family, including DPYSL2, DPYSL3, and DPYSL4, which are essential for axonal growth and neurite morphogenesis [47][48][49] (Figure 3i). Indeed, all tagged SNPs of the CRMP family proteins show stronger association signals with ND than with N0 and NF (Figure 3j).…”

Section: Loci Showing Differential Effects On Tissue Compositionsmentioning

confidence: 99%

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Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Fan

Loughnan

et al. 2021

Preprint

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It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Loci Showing Differential Effects On Tissue Compositionsmentioning

confidence: 99%

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Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Fan

Loughnan

et al. 2021

Preprint

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“…Abnormal neurite outgrowth may cause aberrant polarity, abnormal synaptic plasticity of neuronal cells, and damage to axons and dendrites. Unusual neurodevelopment can induce autism, hyperactivity disorder, dyslexia and so on ( 40 ). Deformed neuronal cell morphology may also cause neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.…”

Section: Discussionmentioning

confidence: 99%

1,800 MHz Radiofrequency Electromagnetic Irradiation Impairs Neurite Outgrowth With a Decrease in Rap1-GTP in Primary Mouse Hippocampal Neurons and Neuro2a Cells

Deng

Chen

et al. 2021

Front. Public Health

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Background: With the global popularity of communication devices such as mobile phones, there are increasing concerns regarding the effect of radiofrequency electromagnetic radiation (RF-EMR) on the brain, one of the most important organs sensitive to RF-EMR exposure at 1,800 MHz. However, the effects of RF-EMR exposure on neuronal cells are unclear. Neurite outgrowth plays a critical role in brain development, therefore, determining the effects of 1,800 MHz RF-EMR exposure on neurite outgrowth is important for exploring its effects on brain development.Objectives: We aimed to investigate the effects of 1,800 MHz RF-EMR exposure for 48 h on neurite outgrowth in neuronal cells and to explore the associated role of the Rap1 signaling pathway.Material and Methods: Primary hippocampal neurons from C57BL/6 mice and Neuro2a cells were exposed to 1,800 MHz RF-EMR at a specific absorption rate (SAR) value of 4 W/kg for 48 h. CCK-8 assays were used to determine the cell viability after 24, 48, and 72 h of irradiation. Neurite outgrowth of primary hippocampal neurons (DIV 2) and Neuro2a cells was observed with a 20 × optical microscope and recognized by ImageJ software. Rap1a and Rap1b gene expressions were detected by real-time quantitative PCR. Rap1, Rap1a, Rap1b, Rap1GAP, and p-MEK1/2 protein expressions were detected by western blot. Rap1-GTP expression was detected by immunoprecipitation. The role of Rap1-GTP was assessed by transfecting a constitutively active mutant plasmid (Rap1-Gly_Val-GFP) into Neuro2a cells.Results: Exposure to 1,800 MHz RF-EMR for 24, 48, and 72 h at 4 W/kg did not influence cell viability. The neurite length, primary and secondary neurite numbers, and branch points of primary mouse hippocampal neurons were significantly impaired by 48-h RF-EMR exposure. The neurite-bearing cell percentage and neurite length of Neuro2a cells were also inhibited by 48-h RF-EMR exposure. Rap1 activity was inhibited by 48-h RF-EMR with no detectable alteration in either gene or protein expression of Rap1. The protein expression of Rap1GAP increased after 48-h RF-EMR exposure, while the expression of p-MEK1/2 protein decreased. Overexpression of constitutively active Rap1 reversed the decrease in Rap1-GTP and the neurite outgrowth impairment in Neuro2a cells induced by 1,800 MHz RF-EMR exposure for 48 h.Conclusion: Rap1 activity and related signaling pathways are involved in the disturbance of neurite outgrowth induced by 48-h 1,800 MHz RF-EMR exposure. The effects of RF-EMR exposure on neuronal development in infants and children deserve greater focus.

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“…Recently, Jeanne et al reported nine patients, including one patient from the first family reported by Ritscher et al, and identified missense variants in DPYSL5 [ 45 , 46 ]. A recurrent de novo p.Glu41Lys was found in eight unrelated patients, while a p.Gly47Arg was identified in one patient from the original RSS family.…”

Section: Human Disorders Associated With Retriever Dysfunctionmentioning

confidence: 99%

Endosomal Recycling Defects and Neurodevelopmental Disorders

Saitoh

2022

Cells

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The quality and quantity of membrane proteins are precisely and dynamically maintained through an endosomal recycling process. This endosomal recycling is executed by two protein complexes: retromer and recently identified retriever. Defects in the function of retromer or retriever cause dysregulation of many membrane proteins and result in several human disorders, including neurodegenerative disorders such as Alzheimer’s disease and Parkinson´s disease. Recently, neurodevelopmental disorders caused by pathogenic variants in genes associated with retriever were identified. This review focuses on the two recycling complexes and discuss their biological and developmental roles and the consequences of defects in endosomal recycling, especially in the nervous system. We also discuss future perspectives of a possible relationship of the dysfunction of retromer and retriever with neurodevelopmental disorders.

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Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

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Cited by 26 publications

References 35 publications

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

Multivariate genome-wide association study on tissue-sensitive diffusion metrics identifies key molecular pathways for axonal growth, synaptogenesis, and astrocyte-mediated neuroinflammation

1,800 MHz Radiofrequency Electromagnetic Irradiation Impairs Neurite Outgrowth With a Decrease in Rap1-GTP in Primary Mouse Hippocampal Neurons and Neuro2a Cells

Endosomal Recycling Defects and Neurodevelopmental Disorders

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