A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

Abstract Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.

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Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21124447 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4447

Author(s):

Pedro A. Lazo ◽

Juan L. García ◽

Paulino Gómez-Puertas ◽

Íñigo Marcos-Alcalde ◽

Cesar Arjona ◽

...

Keyword(s):

Protein Function ◽

De Novo ◽

3D Structure ◽

Unknown Origin ◽

Unknown Etiology ◽

Neurodevelopmental Delay ◽

Calmodulin Binding ◽

Whole Exome ◽

Dynamics Simulations ◽

Frame Duplication

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.

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On the dynamics of some small structural motifs in rRNA upon ligand binding

Journal of the Serbian Chemical Society ◽

10.2298/jsc0801041r ◽

2008 ◽

Vol 73 (1) ◽

pp. 41-53

Author(s):

Aleksandra Rakic ◽

Petar Mitrasinovic

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Binding Sites ◽

De Novo ◽

Reference Structure ◽

Base Pairs ◽

Rna Sequences ◽

Conformational Model ◽

Thermodynamic Variables ◽

Dynamics Simulations

The present study characterizes using molecular dynamics simulations the behavior of the GAA (1186-1188) hairpin triloops with their closing c-g base pairs in large ribonucleoligand complexes (PDB IDs: 1njn, 1nwy, 1jzx). The relative energies of the motifs in the complexes with respect to that in the reference structure (unbound form of rRNA; PDB ID: 1njp) display the trends that agree with those of the conformational parameters reported in a previous study1 utilizing the de novo pseudotorsional (?,?) approach. The RNA regions around the actual RNA-ligand contacts, which experience the most substantial conformational changes upon formation of the complexes were identified. The thermodynamic parameters, based on a two-state conformational model of RNA sequences containing 15, 21 and 27 nucleotides in the immediate vicinity of the particular binding sites, were evaluated. From a more structural standpoint, the strain of a triloop, being far from the specific contacts and interacting primarily with other parts of the ribosome, was established as a structural feature which conforms to the trend of the average values of the thermodynamic variables corresponding to the three motifs defined by the 15-, 21- and 27-nucleotide sequences. From a more functional standpoint, RNA-ligand recognition is suggested to be presumably dictated by the types of ligands in the complexes.

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Study on Morphometric Features of Coronal Suture Along with it Absence and Craniosynostosis

International Journal of Anatomy and Research ◽

10.16965/ijar.2021.172 ◽

2021 ◽

Vol 9 (4) ◽

pp. 8151-8155

Author(s):

Khaleel N ◽

◽

Angadi A V ◽

Muralidhar P S ◽

Shabiya M ◽

...

Keyword(s):

Birth Defect ◽

Cranial Sutures ◽

Coronal Suture ◽

Cranial Suture ◽

Medical Sciences ◽

Hot Climate ◽

Morphometric Features ◽

Metopic Suture ◽

Parietal Bones ◽

The Brain

Background: Cranial sutures are syndesmosis between the cranial bones. The coronal suture is oblique in direction and extends between the frontal and the parietal bones. Craniosynostosis is a rare birth defect that occurs when the coronal suture in the skull fuses prematurely, but the brain continues to grow and develop. This leads to a misshapen head. There are a number of forms of this defect, such as coronal, sagittal, lambdoid, and metopic. Materials and Methods: Total 500 skulls were used for study, coronal suture length measured by thread method, distance between Nasion to bregma and midsupraorbital rim to coronal suture were measured. For finding skull with absence of coronal, sagittal, lambdoid, and metopic suture, we examined many skulls during routine osteology classes of Medical, Dental and other medical sciences students. Around 500 skull observed and we find only one skull with absence of left coronal suture completely. Results: The length of coronal suture was 24.8+1.4cm length, the distance between nasion to bregma was 126.7 +10.25 mm and Midsupraorbital rim to cranial suture was 102.76+8.64mm We have found only one skull with absence of coronal suture. Some of the skulls shows partly fusion of sagittal, coronal sutures. The skull with complete absence of coronal suture showing the features of other sutures clearly and right side of coronal suture is showing the complete suture. The skull was not damaged and it is in perfect condition which was using by students for their osteology study. Conclusion: We found the skull with absence of left coronal suture, which may resulted due to craniosynostosis. It may be due to hot climate in India also might be resulted for absence of suture. KEY WORDS: Birth defect, Skull, Coronal suture, Craniosynostosis.

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Bending of DNA duplexes with mutation motifs

DNA Research ◽

10.1093/dnares/dsz013 ◽

2019 ◽

Vol 26 (4) ◽

pp. 341-352

Author(s):

Michal Růžička ◽

Přemysl Souček ◽

Petr Kulhánek ◽

Lenka Radová ◽

Lenka Fajkusová ◽

...

Keyword(s):

De Novo ◽

Excision Repair ◽

Dna Duplexes ◽

De Novo Mutations ◽

Base Pairs ◽

Inherited Disorders ◽

Cpg Dinucleotides ◽

Human Genes ◽

Base Excision ◽

Dynamics Simulations

Abstract Mutations can be induced by environmental factors but also arise spontaneously during DNA replication or due to deamination of methylated cytosines at CpG dinucleotides. Sites where mutations occur with higher frequency than would be expected by chance are termed hotspots while sites that contain mutations rarely are termed coldspots. Mutations are permanently scanned and repaired by repair systems. Among them, the mismatch repair targets base pair mismatches, which are discriminated from canonical base pairs by probing altered elasticity of DNA. Using biased molecular dynamics simulations, we investigated the elasticity of coldspots and hotspots motifs detected in human genes associated with inherited disorders, and also of motifs with Czech population hotspots and de novo mutations. Main attention was paid to mutations leading to G/T and A+/C pairs. We observed that hotspots without CpG/CpHpG sequences are less flexible than coldspots, which indicates that flexible sequences are more effectively repaired. In contrary, hotspots with CpG/CpHpG sequences exhibited increased flexibility as coldspots. Their mutability is more likely related to spontaneous deamination of methylated cytosines leading to C > T mutations, which are primarily targeted by base excision repair. We corroborated conclusions based on computer simulations by measuring melting curves of hotspots and coldspots containing G/T mismatch.

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Understanding the R882H mutation effects of DNA methyltransferase DNMT3A: a combination of molecular dynamics simulations and QM/MM calculations

RSC Advances ◽

10.1039/c9ra06791d ◽

2019 ◽

Vol 9 (54) ◽

pp. 31425-31434 ◽

Cited By ~ 1

Author(s):

Lanxuan Liu ◽

Ting Shi ◽

Kendall N. Houk ◽

Yi-Lei Zhao

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Dna Methyltransferase ◽

De Novo ◽

Human Beings ◽

Epigenetic Methylation ◽

Key Enzyme ◽

Dynamics Simulations

The AML-related high-frequent R882H mutation of DNA (cytosine-5)-methyltransferase 3A (DNMT3A), a key enzyme for de novo epigenetic methylation in human beings, was characterized by a disturbing conformation of S-adenosylmethionine (SAM).

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Compensatory growth following premature closure of the coronal suture in rabbits

Journal of Neurosurgery ◽

10.3171/jns.1982.57.4.0535 ◽

1982 ◽

Vol 57 (4) ◽

pp. 535-542 ◽

Cited By ~ 42

Author(s):

William J. Babler ◽

John A. Persing ◽

H. Richard Winn ◽

John A. Jane ◽

George T. Rodeheaver

Keyword(s):

Compensatory Growth ◽

Cranial Sutures ◽

Coronal Suture ◽

Skull Morphology ◽

Content Type ◽

Premature Closure ◽

New Zealand White Rabbits ◽

Skull Growth ◽

Skull Deformation ◽

Surgical Release

✓ Premature closure of a cranial suture results in skull deformation characterized by inhibited skull growth in a direction perpendicular to the course of the affected suture. Early surgical release of the closed suture results in a “normal” skull morphology. The present experimental study measured alterations in growth at the transverse cranial sutures that occurred following induced premature closure of the coronal suture and its subsequent release in New Zealand White rabbits. Using roentgenocephalometric methods, growth and morphometric changes were monitored at the frontonasal, coronal, and anterior lambdoid sutures following premature closure of the coronal suture at 9 days of age. The results indicated that premature closure of the coronal suture did not result in compensatory (increased) growth at the other transverse sutures of the vault. In fact, growth at these sutures was significantly reduced. This reduced growth at adjacent transverse sutures was not ameliorated by early surgical release of the fused suture.

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Study of the Lamellar and Micellar Phases of Pluronic F127: A Molecular Dynamics Approach

Processes ◽

10.3390/pr7090606 ◽

2019 ◽

Vol 7 (9) ◽

pp. 606 ◽

Cited By ~ 1

Author(s):

Juan Albano ◽

Damian Grillo ◽

Julio Facelli ◽

Marta Ferraro ◽

Mónica Pickholz

Keyword(s):

Molecular Dynamics ◽

Amorphous Structure ◽

Pluronic F127 ◽

Coarse Grain ◽

Lamellar Thickness ◽

Initial Polymer ◽

Lamellar Phases ◽

New Information ◽

Order Of Magnitude ◽

Dynamics Simulations

In this work, we analyzed the behavior of Pluronic F127 through molecular dynamics simulations at the coarse-grain level, focusing on the micellar and lamellar phases. To this aim, two initial polymer conformations were considered, S-shape and U-shape, for both simulated phases. Through the simulations, we were able to examine the structural and mechanical properties that are difficult to access through experiments. Since no transition between S and U shapes was observed in our simulations, we inferred that all single co-polymers had memory of their initial configuration. Nevertheless, most copolymers had a more complex amorphous structure, where hydrophilic beads were part of the lamellar-like core. Finally, an overall comparison of the micellar a lamellar phases showed that the lamellar thickness was in the same order of magnitude as the micelle diameter (approx. 30 nm). Therefore, high micelle concentration could lead to lamellar formation. With this new information, we could understand lamellae as orderly packed micelles.

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Oxygen Anion Diffusion in Doped Ceria MxCe1-xO2-0.5x (M=Gd, Sm and Pr): A Molecular Dynamics Simulation Study

MRS Advances ◽

10.1557/adv.2019.165 ◽

2019 ◽

Vol 4 (13) ◽

pp. 783-792 ◽

Cited By ~ 1

Author(s):

Neetu Kumari ◽

Uzma Anjum ◽

M. Ali Haider ◽

Suddhastawa Basu

Keyword(s):

Molecular Dynamics ◽

Dopant Concentration ◽

Optimum Concentration ◽

Dynamics Simulation ◽

Doped Ceria ◽

Oxygen Anion ◽

Anion Diffusion ◽

Order Of Magnitude ◽

Pure Ceria ◽

Dynamics Simulations

ABSTRACTMolecular dynamics simulations were utilized to determine the oxygen anion diffusivity in pure ceria (CeO2) and doped ceria MxCe1-xO2-0.5x(M=Gd, Sm and Pr) with varying level of dopant concentration from 5-30% (x = 0.05-0.3). Doping with Gd showed an improvement in oxygen anion diffusivity value by two order of magnitude (D = 4.67x10-8cm2/s at 1173 K) as compared to the undoped ceria (D = 1.33x10-10cm2/s at 1173 K). 10% of doping level was estimated as the optimum concentration of all the dopants at which all of the doped ceria materials showed maximum diffusivity of oxygen anion. Among the three dopants studied, Pr was observed to show maximum diffusivity of oxygen anion in the temperature range of 773-1173 K of simulations.

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