A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes a neurodevelopmental disorder with microcephaly and speech delay

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

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Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?

Genes ◽

10.3390/genes13010078 ◽

2021 ◽

Vol 13 (1) ◽

pp. 78

Author(s):

Nuno Maia ◽

Maria João Nabais Sá ◽

Cláudia Oliveira ◽

Flávia Santos ◽

Célia Azevedo Soares ◽

...

Keyword(s):

Dna Repair ◽

De Novo ◽

Biochemical Study ◽

Neurodevelopmental Disorder ◽

Chromosome Instability ◽

Pathogenic Variant ◽

Fanconi Anaemia ◽

Cellular Phenotype ◽

Full Spectrum ◽

New Genotype

We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient’s chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype–phenotype correlations and motivating the biochemical study of the underlying mechanisms.

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The Role of Protein Arginine Methylation as Post-Translational Modification on Actin Cytoskeletal Components in Neuronal Structure and Function

Cells ◽

10.3390/cells10051079 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1079

Author(s):

Britta Qualmann ◽

Michael M. Kessels

Keyword(s):

Actin Filament ◽

Regulatory Mechanism ◽

De Novo ◽

Arginine Methylation ◽

Loss Of Function ◽

Filament Formation ◽

Post Translational Modification ◽

Neuronal Structure ◽

Actin Nucleation ◽

Protein Arginine Methylation

The brain encompasses a complex network of neurons with exceptionally elaborated morphologies of their axonal (signal-sending) and dendritic (signal-receiving) parts. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly and dynamics thus require tight temporal and spatial control. Such control is particularly effective at the level of regulating actin nucleation-promoting factors, as these are key components for filament formation. Arginine methylation represents an important post-translational regulatory mechanism that had previously been mainly associated with controlling nuclear processes. We will review and discuss emerging evidence from inhibitor studies and loss-of-function models for protein arginine methyltransferases (PRMTs), both in cells and whole organisms, that unveil that protein arginine methylation mediated by PRMTs represents an important regulatory mechanism in neuritic arbor formation, as well as in dendritic spine induction, maturation and plasticity. Recent results furthermore demonstrated that arginine methylation regulates actin cytosolic cytoskeletal components not only as indirect targets through additional signaling cascades, but can also directly control an actin nucleation-promoting factor shaping neuronal cells—a key process for the formation of neuronal networks in vertebrate brains.

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Parallel assembly of actin and tropomyosin, but not myosin II, during de novo actin filament formation in live mice

Journal of Cell Science ◽

10.1242/jcs.212654 ◽

2018 ◽

Vol 131 (6) ◽

pp. jcs212654 ◽

Cited By ~ 12

Author(s):

Andrius Masedunskas ◽

Mark A. Appaduray ◽

Christine A. Lucas ◽

María Lastra Cagigas ◽

Marco Heydecker ◽

...

Keyword(s):

Actin Filament ◽

De Novo ◽

Myosin Ii ◽

Filament Formation ◽

Parallel Assembly

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Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures

Human Genome Variation ◽

10.1038/s41439-021-00176-4 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Keiko Shimojima Yamamoto ◽

Tomoe Yanagishita ◽

Hisako Yamamoto ◽

Yusaku Miyamoto ◽

Miho Nagata ◽

...

Keyword(s):

Developmental Delay ◽

Neurodevelopmental Disorders ◽

Japanese Patient ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Pathogenic Variant ◽

Adult Patients ◽

Facial Features ◽

Initial Report

AbstractA recurrent de novo pathogenic variant of WASF1, NM_003931:c.1516C>T [p.Arg506*], was identified in a 6-year-old female Japanese patient with severe developmental delay, hypotonia, hyperkinetic behavior, and distinctive facial features. The initial report of five adult patients with WASF1 variants was the only previous report regarding variants of this gene; this is the second such report, reaffirming that rare but recurrent truncating variants of WASF1 are associated with severe neurodevelopmental disorders.

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Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Human Genetics ◽

10.1007/s00439-021-02283-2 ◽

2021 ◽

Author(s):

Ilaria Parenti ◽

◽

Daphné Lehalle ◽

Caroline Nava ◽

Erin Torti ◽

...

Keyword(s):

Intellectual Disability ◽

Behavioral Problems ◽

Neuronal Development ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Speech Delay ◽

Nurd Complex ◽

Behavioral Disturbances ◽

Nucleosome Remodeling ◽

Motor Delay

AbstractLocated in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Genome Medicine ◽

10.1186/s13073-021-00900-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Ilaria Mannucci ◽

Nghi D. P. Dang ◽

Hannes Huber ◽

Jaclyn B. Murry ◽

Jeff Abramson ◽

...

Keyword(s):

De Novo ◽

Clinical Course ◽

Neurodevelopmental Disorder ◽

Global Developmental Delay ◽

Helicase Activity ◽

Speech Impairment ◽

Human Phenotype ◽

Missense Variants ◽

The Impact ◽

Global Translation

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

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Stimulus-response uncoupling in the neutrophil. Adenosine A2-receptor occupancy inhibits the sustained, but not the early, events of stimulus transduction in human neutrophils by a mechanism independent of actin-filament formation

Biochemical Journal ◽

10.1042/bj2810631 ◽

1992 ◽

Vol 281 (3) ◽

pp. 631-635 ◽

Cited By ~ 28

Author(s):

B N Cronstein ◽

K A Haines

Keyword(s):

Actin Filament ◽

Adenosine Receptor ◽

Actin Filaments ◽

Cytochalasin B ◽

Receptor Occupancy ◽

Neutrophil Activation ◽

Filament Formation ◽

Stimulus Response ◽

Adenosine A2 Receptor ◽

A2 Receptors

Generation of superoxide anion (O2-) in response to occupancy of neutrophil chemoattractant receptors requires both early events (‘triggering’) and sustained signals (‘activation’). We have previously demonstrated that occupancy of adenosine A2 receptors inhibits O2- generation by neutrophils. In parallel, adenosine-receptor occupancy promotes association of bound N-formylmethionyl-leucyl-phenylalanine (fMLP) receptors with the cytoskeleton, a process associated with termination of neutrophil activation (stimulus-response uncoupling). We undertook this study to determine whether inhibition of neutrophil function by adenosine-receptor occupancy requires intact actin filaments and to examine the effect of adenosine-receptor occupancy on the stimulated generation of intracellular signals involved in neutrophil triggering and activation. Occupancy of adenosine A2 receptors by 5′-N-ethylcarboxamidoadenosine (NECA, 1 microM) significantly increased (130 +/- 1% of control, P less than 0.001, n = 3) association of [3H]fMLP with cytoskeletal preparations. Cytochalasin B (5 micrograms/ml), an agent which disrupts actin filaments, completely blocked association of [3H]fMLP with cytoskeletal preparations, as previously reported. However, NECA markedly increased association of [3H]fMLP with the cytoskeleton even in the presence of cytochalasin B (P less than 0.0002). Moreover, NECA did not significantly affect either the early (30s) or the late (5 min) formation of actin filaments after stimulation by chemoattractant (fMLP, 0.1-100 nM). Cytochalasin B markedly inhibited actin-filament formation by stimulated neutrophils, and NECA did not reverse the effect of cytochalasin B on actin-filament formation. Adenosine-receptor occupancy did not affect the rapid peak in diacylglycerol generation (less than or equal to 15 s) from either [3H]arachidonate- or [14C]glycerol-labelled phospholipid pools. However, as would be predicted if occupancy of the adenosine receptor was a signal for early termination of cell activation, NECA (1 microM) markedly diminished the slow sustained generation of diacylglycerol. These results suggest that adenosine-A2-receptor occupancy does not affect triggering of the neutrophil, but that occupancy of adenosine receptors is an early signal for the termination of neutrophil activation, i.e. the ‘premature’ finish of signal transduction. Moreover, these data indicate that at least two pathways are available for increasing the association of ligated chemoattractant receptors with the cytoskeleton of neutrophils: F-actin-dependent and -independent.

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