scholarly journals Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay

2020 ◽  
Vol 29 (9) ◽  
pp. 1537-1546
Author(s):  
Yan Huang ◽  
Xiao Mao ◽  
Richard H van Jaarsveld ◽  
Li Shu ◽  
Paulien A Terhal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Motor Development ◽  
Actin Polymerization ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
De Novo Mutations ◽  
Lower Efficiency ◽  
Capping Protein ◽  
Actin Capping Protein ◽  
Actin Capping

Abstract The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous de novo mutations in CAPZA2 (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures. CAPZA2 encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and CAPZA2 encodes the α2 subunit. The single orthologue of CAPZA genes in Drosophila is cpa. Loss of cpa leads to lethality in early development and expression of the human reference; CAPZA2 rescues this lethality. However, the two CAPZA2 variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the CAPZA2 variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in CAPZA2 lead to a non-syndromic neurodevelopmental disorder in children.

scholarly journals Regulation of Sodium Channel Activity by Capping of Actin Filaments

2003 ◽  
Vol 14 (4) ◽  
pp. 1709-1716 ◽  
Author(s):  
Ekaterina V. Shumilina ◽  
Yuri A. Negulyaev ◽  
Elena A. Morachevskaya ◽  
Horst Hinssen ◽  
Sofia Yu Khaitlina
Keyword(s):  
Plasma Membrane ◽  
Sodium Channel ◽  
Actin Filaments ◽  
Actin Polymerization ◽  
Actin Dynamics ◽  
Channel Activity ◽  
Capping Protein ◽  
Channel Inactivation ◽  
Actin Capping Protein ◽  
Actin Capping

Ion transport in various tissues can be regulated by the cortical actin cytoskeleton. Specifically, involvement of actin dynamics in the regulation of nonvoltage-gated sodium channels has been shown. Herein, inside-out patch clamp experiments were performed to study the effect of the heterodimeric actin capping protein CapZ on sodium channel regulation in leukemia K562 cells. The channels were activated by cytochalasin-induced disruption of actin filaments and inactivated by G-actin under ionic conditions promoting rapid actin polymerization. CapZ had no direct effect on channel activity. However, being added together with G-actin, CapZ prevented actin-induced channel inactivation, and this effect occurred at CapZ/actin molar ratios from 1:5 to 1:100. When actin was allowed to polymerize at the plasma membrane to induce partial channel inactivation, subsequent addition of CapZ restored the channel activity. These results can be explained by CapZ-induced inhibition of further assembly of actin filaments at the plasma membrane due to the modification of actin dynamics by CapZ. No effect on the channel activity was observed in response to F-actin, confirming that the mechanism of channel inactivation does not involve interaction of the channel with preformed filaments. Our data show that actin-capping protein can participate in the cytoskeleton-associated regulation of sodium transport in nonexcitable cells.

scholarly journals Actin-capping protein promotes microtubule stability by antagonizing the actin activity of mDia1

2012 ◽  
Vol 23 (20) ◽  
pp. 4032-4040 ◽  
Author(s):  
Francesca Bartolini ◽  
Nagendran Ramalingam ◽  
Gregg G. Gundersen
Keyword(s):  
Actin Filaments ◽  
Actin Polymerization ◽  
Dependent Manner ◽  
Proliferating Cells ◽  
Capping Protein ◽  
Microtubule Stability ◽  
Selective Stabilization ◽  
Actin Capping Protein ◽  
Actin Capping ◽  
Interfering Rna

In migrating fibroblasts, RhoA and its effector mDia1 regulate the selective stabilization of microtubules (MTs) polarized in the direction of migration. The conserved formin homology 2 domain of mDia1 is involved both in actin polymerization and MT stabilization, and the relationship between these two activities is unknown. We found that latrunculin A (LatA) and jasplakinolide, actin drugs that release mDia1 from actin filament barbed ends, stimulated stable MT formation in serum-starved fibroblasts and caused a redistribution of mDia1 onto MTs. Knockdown of mDia1 by small interfering RNA (siRNA) prevented stable MT induction by LatA, whereas blocking upstream Rho or integrin signaling had no effect. In search of physiological regulators of mDia1, we found that actin-capping protein induced stable MTs in an mDia1-dependent manner and inhibited the translocation of mDia on the ends of growing actin filaments. Knockdown of capping protein by siRNA reduced stable MT levels in proliferating cells and in starved cells stimulated with lysophosphatidic acid. These results show that actin-capping protein is a novel regulator of MT stability that functions by antagonizing mDia1 activity toward actin filaments and suggest a novel form of actin–MT cross-talk in which a single factor acts sequentially on actin and MTs.

scholarly journals A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 344 ◽  
Author(s):  
Emanuela Leonardi ◽  
Mariagrazia Bellini ◽  
Maria C. Aspromonte ◽  
Roberta Polli ◽  
Anna Mercante ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Status Epilepticus ◽  
Behavioral Problems ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Somatic Mosaicism ◽  
Coiled Coil ◽  
Loss Of Function ◽  
De Novo Mutations

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

scholarly journals Capping protein regulates actin dynamics during cytokinetic midbody maturation

2018 ◽  
Vol 115 (9) ◽  
pp. 2138-2143 ◽  
Author(s):  
Stephen J. Terry ◽  
Federico Donà ◽  
Paul Osenberg ◽  
Jeremy G. Carlton ◽  
Ulrike S. Eggert
Keyword(s):  
Actin Filaments ◽  
Actin Polymerization ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Capping Protein ◽  
Cytoskeletal Remodeling ◽  
Daughter Cells ◽  
Actin Capping Protein ◽  
Activity Loss ◽  
Actin Capping

During cytokinesis, a cleavage furrow generated by actomyosin ring contraction is restructured into the midbody, a platform for the assembly of the abscission machinery that controls the final separation of daughter cells. The polymerization state of F-actin is important during assembly, ingression, disassembly, and closure of the contractile ring and for the cytoskeletal remodeling that accompanies midbody formation and progression to abscission. Actin filaments must be cleared from the abscission sites before the final cut can take place. Although many conserved proteins interact with and influence the polymerization state of actin filaments, it is poorly understood how they regulate cytokinesis in higher eukaryotes. We report here that the actin capping protein (CP), a barbed end actin binding protein, participates in the control of actin polymerization during later stages of cytokinesis in human cells. Cells depleted of CP furrow and form early midbodies, but they fail cytokinesis. Appropriate recruitment of the ESCRT-III abscission machinery to the midbody is impaired, preventing the cell from progressing to the abscission stage. To generate actin filaments of optimal length, different actin nucleators, such as formins, balance CP’s activity. Loss of actin capping activity leads to excessive accumulation of formin-based linear actin filaments. Depletion of the formin FHOD1 results in partial rescue of CP-induced cytokinesis failure, suggesting that it can antagonize CP activity during midbody maturation. Our work suggests that the actin cytoskeleton is remodeled in a stepwise manner during cytokinesis, with different regulators at different stages required for successful progression to abscission.

scholarly journals The alpha and beta subunits of nematode actin capping protein function in yeast.

1993 ◽  
Vol 4 (9) ◽  
pp. 907-917 ◽  
Author(s):  
J A Waddle ◽  
J A Cooper ◽  
R H Waterston
Keyword(s):  
Actin Cytoskeleton ◽  
Protein Function ◽  
Actin Polymerization ◽  
Beta Subunits ◽  
Wild Type ◽  
Capping Protein ◽  
Actin Capping Protein ◽  
Actin Capping ◽  
Chicken Skeletal Muscle ◽  
Null Mutants

We cloned and analyzed two genes, cap-1 and cap-2, which encode the alpha and beta subunits of Caenorhabditis elegans capping protein (CP). The nematode CP subunits are 55% (cap-1) and 66% (cap-2) identical to the chicken CP subunits and 32% (cap-1) and 48% (cap-2) identical to the yeast CP subunits. Purified nematode CP made by expression of both subunits in yeast is functionally similar to chicken skeletal muscle CP in two different actin polymerization assays. The abnormal cell morphology and disorganized actin cytoskeleton of yeast CP null mutants are restored to wild-type by expression of the nematode CP subunits. Expression of the nematode CP alpha or beta subunit is sufficient to restore viability to yeast cap1 sac6 or cap2 sac6 double mutants, respectively. Therefore, despite evolution of the nematode actin cytoskeleton to a state far more complex than that of yeast, one important component can function in both organisms.

scholarly journals A familial case of CAMK2B mutation with variable expressivity

2021 ◽  
Vol 9 ◽  
pp. 2050313X2199098
Author(s):  
Paige Heiman ◽  
Sarah Drewes ◽  
Lina Ghaloul-Gonzalez
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Clinical Manifestations ◽  
Cerebellar Atrophy ◽  
Global Developmental Delay ◽  
De Novo Mutations ◽  
Phenotypic Spectrum ◽  
Behavioral Abnormalities ◽  
Intrafamilial Variability

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

Structural insights into the regulation of actin capping protein by twinfilin C-terminal tail

2021 ◽  
pp. 166891
Author(s):  
Shuichi Takeda ◽  
Ryotaro Koike ◽  
Ikuko Fujiwara ◽  
Akihiro Narita ◽  
Makoto Miyata ◽  
...  
Keyword(s):  
Capping Protein ◽  
Actin Capping Protein ◽  
Actin Capping ◽  
Structural Insights

scholarly journals CapZ integrates several signaling pathways in response to mechanical stiffness

2019 ◽  
Vol 151 (5) ◽  
pp. 660-669 ◽  
Author(s):  
Christopher Solís ◽  
Brenda Russell
Keyword(s):  
Mechanical Load ◽  
Phosphorylation Site ◽  
Tight Binding ◽  
Neonatal Rat ◽  
Actin Binding ◽  
Mechanical Stimuli ◽  
Muscle Adaptation ◽  
Capping Protein ◽  
Actin Capping Protein ◽  
Actin Capping

Muscle adaptation is a response to physiological demand elicited by changes in mechanical load, hormones, or metabolic stress. Cytoskeletal remodeling processes in many cell types are thought to be primarily regulated by thin filament formation due to actin-binding accessory proteins, such as the actin-capping protein. Here, we hypothesize that in muscle, the actin-capping protein (named CapZ) integrates signaling by a variety of pathways, including phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP2) binding, to regulate muscle fiber growth in response to mechanical load. To test this hypothesis, we assess mechanotransduction signaling that regulates muscle growth using neonatal rat ventricular myocytes cultured on substrates with the stiffness of the healthy myocardium (10 kPa), fibrotic myocardium (100 kPa), or glass. We investigate how PIP2 signaling affects CapZ using the PIP2 sequestering agent neomycin and the effect of PKC-mediated CapZ phosphorylation using the PKC-activating drug phorbol 12-myristate 13-acetate (PMA). Molecular simulations suggest that close interactions between PIP2 and the β-tentacle of CapZ are modified by phosphorylation at T267. Fluorescence recovery after photobleaching (FRAP) demonstrates that the kinetic binding constant of CapZ to sarcomeric thin filaments in living muscle cells increases with stiffness or PMA treatment but is diminished by PIP2 reduction. Furthermore, CapZ with a deletion of the β-tentacle that lacks the phosphorylation site T267 shows increased FRAP kinetics with lack of sensitivity to PMA treatment or PIP2 reduction. Förster resonance energy transfer (FRET) probes the molecular interactions between PIP2 and CapZ, which are decreased by PIP2 availability or by the β-tentacle truncation. These data suggest that CapZ is bound to actin tightly in the idle, locked state, with little phosphorylation or PIP2 binding. However, this tight binding is loosened in growth states triggered by mechanical stimuli such as substrate stiffness, which may have relevance to fibrotic heart disease.

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