scholarly journals Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

2022 ◽  
Vol 14 ◽  
Author(s):  
Bipan K. Deb ◽  
Helen S. Bateup
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neurodevelopmental Disorders ◽  
Somatic Mutations ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Model Systems ◽  
Loss Of Function ◽  
And Function ◽  
The Impact

Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

scholarly journals Codon harmonization reduces amino acid misincorporation in bacterially expressed P. falciparum proteins and improves their immunogenicity

AMB Express ◽  
2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Neeraja Punde ◽  
Jennifer Kooken ◽  
Dagmar Leary ◽  
Patricia M. Legler ◽  
Evelina Angov
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Codon Usage ◽  
Dna Sequences ◽  
Structural Integrity ◽  
Host Cells ◽  
Loss Of Function ◽  
Species Specific ◽  
And Function ◽  
The Impact

Abstract Codon usage frequency influences protein structure and function. The frequency with which codons are used potentially impacts primary, secondary and tertiary protein structure. Poor expression, loss of function, insolubility, or truncation can result from species-specific differences in codon usage. “Codon harmonization” more closely aligns native codon usage frequencies with those of the expression host particularly within putative inter-domain segments where slower rates of translation may play a role in protein folding. Heterologous expression of Plasmodium falciparum genes in Escherichia coli has been a challenge due to their AT-rich codon bias and the highly repetitive DNA sequences. Here, codon harmonization was applied to the malarial antigen, CelTOS (Cell-traversal protein for ookinetes and sporozoites). CelTOS is a highly conserved P. falciparum protein involved in cellular traversal through mosquito and vertebrate host cells. It reversibly refolds after thermal denaturation making it a desirable malarial vaccine candidate. Protein expressed in E. coli from a codon harmonized sequence of P. falciparum CelTOS (CH-PfCelTOS) was compared with protein expressed from the native codon sequence (N-PfCelTOS) to assess the impact of codon usage on protein expression levels, solubility, yield, stability, structural integrity, recognition with CelTOS-specific mAbs and immunogenicity in mice. While the translated proteins were expected to be identical, the translated products produced from the codon-harmonized sequence differed in helical content and showed a smaller distribution of polypeptides in mass spectra indicating lower heterogeneity of the codon harmonized version and fewer amino acid misincorporations. Substitutions of hydrophobic-to-hydrophobic amino acid were observed more commonly than any other. CH-PfCelTOS induced significantly higher antibody levels compared with N-PfCelTOS; however, no significant differences in either IFN-γ or IL-4 cellular responses were detected between the two antigens.

scholarly journals Normative range parenting and the developing brain: a scoping review of the literature

2019 ◽  
Author(s):  
Madeline Farber ◽  
Dylan Gee ◽  
Ahmad R. Hariri
Keyword(s):  
Mental Health ◽  
Brain Development ◽  
Scoping Review ◽  
Developmental Trajectories ◽  
Future Research ◽  
Risk And Resilience ◽  
Abuse And Neglect ◽  
Brain Structure And Function ◽  
And Function ◽  
The Impact

Studies of early adversity such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in brain development and mental health. However, the impact of normative range variability in caregiving on such biobehavioral processes remains poorly understood. Thus, we lack an essential foundation for understanding broader, population-representative developmental mechanisms of risk and resilience. Here, we conduct a scoping review of the extant literature centered on the question, “Is variability in normative range parenting associated with variability in brain structure and function?” After removing duplicates and screening by title, abstract, and full-text, 23 records were included in a qualitative review. The most striking outcome of this review was not only how few studies have explored associations between brain development and normative range parenting, but also how little methodological consistency exists across published studies. In light of these limitations, we propose recommendations for future research on normative range parenting and brain development. In doing so, we hope to facilitate evidence-based research that will help inform policies and practices that yield optimal developmental trajectories and mental health.

Focal Cortical Dysplasias

2017 ◽  
Author(s):  
Ali Mahta ◽  
Peter B. Crino
Keyword(s):  
Brain Development ◽  
Somatic Mutations ◽  
Mammalian Target Of Rapamycin ◽  
Intractable Epilepsy ◽  
Cell Types ◽  
Current Belief ◽  
Type Ia ◽  
Cortical Dysplasias ◽  
Refractory Seizures ◽  
Unique Cell

Focal cortical dysplasias (FCDs) are common malformations of cerebral cortical development that are highly associated with medically intractable epilepsy. FCDs have been classified according to neuropathological subtypes (type Ia, Ib, IIA, IIb, and III) based on the severity of cytoarchitectural disruption, and the presence of unique cell types (e.g., balloon cells). Most FCDs can be detected by neuroimaging studies and will require respective epilepsy surgery to cure refractory seizures. The pathogenesis of FCDs remains to be defined, although current belief is that these lesions result from sporadic somatic mutations occurring in brain development. A link to the mammalian target of rapamycin cascade has been defined for some FCD subtypes.

scholarly journals Determining the impact of putative loss-of-function variants in protein-coding genes

2017 ◽  
Author(s):  
Suganthi Balasubramanian ◽  
Yao Fu ◽  
Mayur Pawashe ◽  
Patrick McGillivray ◽  
Mike Jin ◽  
...  
Keyword(s):  
De Novo ◽  
Mendelian Disease ◽  
Loss Of Function ◽  
Homozygous State ◽  
Driver Genes ◽  
Protein Coding ◽  
Disease Gene Discovery ◽  
Human Genes ◽  
Using Data ◽  
The Impact

AbstractVariants predicted to result in the loss of function (LoF) of human genes have attracted interest because of their clinical impact and surprising prevalence in healthy individuals. Here, we present ALoFT (Annotation of Loss-of-Function Transcripts), a method to annotate and predict the disease-causing potential of LoF variants. Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between LoF variants deleterious as heterozygotes and those causing disease only in the homozygous state. Investigation of variants discovered in healthy populations suggests that each individual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. When applied to de novo pLoF variants in autism-affected families, ALoFT distinguishes between deleterious variants in patients and benign variants in unaffected siblings. Finally, analysis of somatic variants in > 6,500 cancer exomes shows that pLoF variants predicted to be deleterious by ALoFT are enriched in known driver genes.

scholarly journals Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiucui Li ◽  
Shijia Bao ◽  
Wei Wang ◽  
Xulai Shi ◽  
Ying Hu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
De Novo ◽  
Basolateral Membrane ◽  
Intractable Epilepsy ◽  
Chinese Patient ◽  
Renal Tubules ◽  
Variable Degree ◽  
Mild Intellectual Disability ◽  
Severity Of The Disease

A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia. Cyclin M2 (CNNM2) proteins, as a member of magnesium (Mg2+) transporters, were found along the basolateral membrane of distal renal tubules and involved in the reabsorption of Mg2+. Homozygous and heterozygous variants in CNNM2 reported so far were responsible for a variable degree of hypomagnesemia, several of which also showed varying degrees of neurological phenotypes such as intellectual disability and epilepsy. Here, we report a de novo heterozygous CNNM2 variant (c.2228C > T, p.Ser743Phe) in a Chinese patient, which is the variant located in the cyclic nucleotide monophosphate-binding homology (CNBH) domain of CNNM2 proteins. The patient presented with mild intellectual disability and refractory epilepsy but without hypomagnesemia. Thus, we reviewed the literature and analyzed the phenotypes related to CNNM2 variants, and then concluded that the number of variant alleles and the changed protein domains correlates with the severity of the disease, and speculated that the CNBH domain of CNNM2 possibly plays a limited role in Mg2+ transport but a significant role in brain development. Furthermore, it can be speculated that neurological phenotypes such as intellectual disability and seizures can be purely caused by CNNM2 variants.

scholarly journals Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2314
Author(s):  
Lisa Kurmann ◽  
Michal Okoniewski ◽  
Raghvendra K. Dubey
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Human Brain ◽  
Neurovascular Unit ◽  
Active Role ◽  
Migration Activity ◽  
Akt Phosphorylation ◽  
And Function ◽  
The Impact

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.

scholarly journals Unraveling Human Brain Development and Evolution Using Organoid Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarah Fernandes ◽  
Davis Klein ◽  
Maria C. Marchetto
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Brain Region ◽  
Model Systems ◽  
Transcriptional Signature ◽  
Human Brain Development ◽  
Advanced Stages ◽  
Brain Organoid ◽  
Development And Evolution ◽  
Human Specific

Brain organoids are proving to be physiologically relevant models for studying human brain development in terms of temporal transcriptional signature recapitulation, dynamic cytoarchitectural development, and functional electrophysiological maturation. Several studies have employed brain organoid technologies to elucidate human-specific processes of brain development, gene expression, and cellular maturation by comparing human-derived brain organoids to those of non-human primates (NHPs). Brain organoids have been established from a variety of NHP pluripotent stem cell (PSC) lines and many protocols are now available for generating brain organoids capable of reproducibly representing specific brain region identities. Innumerous combinations of brain region specific organoids derived from different human and NHP PSCs, with CRISPR-Cas9 gene editing techniques and strategies to promote advanced stages of maturation, will successfully establish complex brain model systems for the accurate representation and elucidation of human brain development. Identified human-specific processes of brain development are likely vulnerable to dysregulation and could result in the identification of therapeutic targets or disease prevention strategies. Here, we discuss the potential of brain organoids to successfully model human-specific processes of brain development and explore current strategies for pinpointing these differences.

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