scholarly journals O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability

2020 ◽  
Vol 11 ◽  
Author(s):  
Daniel Konzman ◽  
Lara K. Abramowitz ◽  
Agata Steenackers ◽  
Mana Mohan Mukherjee ◽  
Hyun-Jin Na ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Parental Stress ◽  
De Novo ◽  
Genetic Disorder ◽  
Nutrient Sensing ◽  
Model Organisms ◽  
Transcriptional Networks ◽  
Hexosamine Biosynthetic Pathway ◽  
Human Genetic Disorder ◽  
Glcnac Transferase

Cellular identity in multicellular organisms is maintained by characteristic transcriptional networks, nutrient consumption, energy production and metabolite utilization. Integrating these cell-specific programs are epigenetic modifiers, whose activity is often dependent on nutrients and their metabolites to function as substrates and co-factors. Emerging data has highlighted the role of the nutrient-sensing enzyme O-GlcNAc transferase (OGT) as an epigenetic modifier essential in coordinating cellular transcriptional programs and metabolic homeostasis. OGT utilizes the end-product of the hexosamine biosynthetic pathway to modify proteins with O-linked β-D-N-acetylglucosamine (O-GlcNAc). The levels of the modification are held in check by the O-GlcNAcase (OGA). Studies from model organisms and human disease underscore the conserved function these two enzymes of O-GlcNAc cycling play in transcriptional regulation, cellular plasticity and mitochondrial reprogramming. Here, we review these findings and present an integrated view of how O-GlcNAc cycling may contribute to cellular memory and transgenerational inheritance of responses to parental stress. We focus on a rare human genetic disorder where mutant forms of OGT are inherited or acquired de novo. Ongoing analysis of this disorder, OGT- X-linked intellectual disability (OGT-XLID), provides a window into how epigenetic factors linked to O-GlcNAc cycling may influence neurodevelopment.

scholarly journals Kabuki Syndrome: Identification of Two Novel Variants in KMT2Dand KDM6A

2021 ◽  
pp. 1-9
Author(s):  
Mehrnoosh Khodaeian ◽  
Ehsan Jafarinia ◽  
Fatemeh Bitarafan ◽  
Shohreh Shafeii ◽  
Navid Almadani ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Kabuki Syndrome ◽  
Functional Studies ◽  
Large Deletions ◽  
Whole Exome ◽  
Functionally Impaired ◽  
And Function

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

scholarly journals A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability

2021 ◽  
Vol 118 (16) ◽  
pp. e2018740118
Author(s):  
Abdelhalim Loukil ◽  
Chloe Barrington ◽  
Sarah C. Goetz
Keyword(s):  
Human Disease ◽  
Cellular Response ◽  
De Novo ◽  
Genetic Disorder ◽  
Structural Defects ◽  
De Novo Mutations ◽  
Superresolution Microscopy ◽  
Mother Centriole ◽  
Multistep Process ◽  
Human Genetic Disorder

Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified Tau tubulin kinase 2 (TTBK2) as a key regulator of ciliogenesis. Here, using CRISPR kinome and biotin identification screening, we identify the CK2 catalytic subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Superresolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages. Csnk2a1 mutant cilia are longer than those of control cells, showing instability at the tip associated with ciliary actin cytoskeleton changes. These cilia also abnormally accumulate key cilia assembly and SHH-related proteins. De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells causes ciliary structural defects. Our findings provide insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance of cilia instability in human disease.

scholarly journals A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

2020 ◽  
Author(s):  
Abdelhalim Loukil ◽  
Chloe Barrington ◽  
Sarah C. Goetz
Keyword(s):  
Human Disease ◽  
Cellular Response ◽  
Primary Cilia ◽  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Super Resolution ◽  
Structural Defects ◽  
Mother Centriole ◽  
Human Genetic Disorder

ABSTRACTCilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. Here, using CRISPR kinome screening, we identify the CK2 subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Super-resolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages where it physically interacts with TTBK2. Further, Csnk2a1 knockout partially corrects defects in cilia formation and length in Ttbk2 hypomorphic cells. Csnk2a1 mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip. Csnk2a1 mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO). De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells cause ciliary structural defects. Our findings provide new insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease.SIGNIFICANCE STATEMENTPrimary cilia (PC) are sensory organelles that play essential roles during development and adulthood. Abnormal functioning of PC causes human disorders called ciliopathies. Hence, a thorough understanding of the molecular regulation of PC is critical. Our findings highlight CSNK2A1 as a novel modulator of cilia trafficking and stability, tightly related to TTBK2 function. Enriched at the centrosome, CSNK2A1 prevents abnormal accumulation of key ciliary proteins, instability at the tip, and aberrant activation of the Sonic Hedgehog pathway. Further, we establish that Csnk2a1 mutations associated with Okur-Chung neurodevelopmental disorder (OCNDS) alter cilia morphology. Thus, we report a potential linkage between CSNK2A1 ciliary function and OCNDS.

scholarly journals Identification of de novo EP300 and PLAU variants in a patient with Rubinstein–Taybi syndrome-related arterial vasculopathy and skeletal anomaly

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jong Eun Park ◽  
Eunmi Kim ◽  
Dong-Won Lee ◽  
Taek Kyu Park ◽  
Min Sun Kim ◽  
...  
Keyword(s):  
De Novo ◽  
Binding Protein ◽  
Genetic Disorder ◽  
Vascular Occlusion ◽  
Matrix Remodeling ◽  
Creb Binding Protein ◽  
Skeletal Anomaly ◽  
Craniofacial Features ◽  
Peripheral Arterial ◽  
Human Genetic Disorder

AbstractRubinstein–Taybi syndrome (RSTS) is a human genetic disorder characterized by distinctive craniofacial features, broad thumbs and halluces, and intellectual disability. Mutations in the CREB binding protein (CREBBP) and E1A binding protein p300 (EP300) are the known causes of RSTS disease. EP300 regulates transcription via chromatin remodeling and plays an important role in cell proliferation and differentiation. Plasminogen activator, urokinase (PLAU) encodes a serine protease that converts plasminogen to plasmin and is involved in several biological processes such as the proteolysis of extracellular matrix-remodeling proteins and the promotion of vascular permeability and angiogenesis. Recently, we discovered a patient who presented with RSTS-related skeletal anomaly and peripheral arterial vasculopathy. To investigate the genetic cause of the disease, we performed trio whole genome sequencing of the genomic DNA from the proband and the proband’s parents. We identified two de novo variants coined c.1760T>G (p.Leu587Arg) and c.664G>A (p.Ala222Thr) in EP300 and PLAU, respectively. Furthermore, functional loss of EP300a and PLAUb in zebrafish synergistically affected the intersegmental vessel formation and resulted in the vascular occlusion phenotype. Therefore, we hypothesize that the de novo EP300 variant may have caused RSTS, while both the identified EP300 and PLAU variants may have contributed to the patient’s vascular phenotype.

TSC1 and TSC2: genes that are mutated in the human genetic disorder tuberous sclerosis

2003 ◽  
Vol 31 (3) ◽  
pp. 592-596 ◽  
Author(s):  
J.R. Sampson
Keyword(s):  
Tuberous Sclerosis ◽  
Positional Cloning ◽  
Therapeutic Potential ◽  
Genetic Disorder ◽  
Cell Types ◽  
Model Organisms ◽  
Related Disorder ◽  
Functional Complex ◽  
Phosphoinositide 3 Kinase ◽  
Human Genetic Disorder

The tuberous sclerosis complex genes TSC1 and TSC2 were first identified by positional cloning strategies in the heritable human disorder tuberous sclerosis. They encode previously unknown proteins, termed hamartin and tuberin respectively, that form a functional complex. The phenotypic manifestations of tuberous sclerosis are extremely diverse and suggest normal roles for TSC1 and TSC2 in regulating the growth, proliferation, migration and differentiation of many cell types. Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected. Most promisingly, the hamartin–tuberin complex has been shown to function as a negtive regulator of the insulin receptor/phosphoinositide 3-kinase/S6 kinase pathway. Drugs that act to inhibit this pathway may have therapeutic potential for tuberous sclerosis and the related disorder lymphangioleiomyomatosis.

scholarly journals Removing the bad apples: A simple bioinformatic method to improve loci‐recovery in de novo RADseq data for non‐model organisms

2021 ◽  
Author(s):  
José Cerca ◽  
Marius F. Maurstad ◽  
Nicolas C. Rochette ◽  
Angel G. Rivera‐Colón ◽  
Niraj Rayamajhi ◽  
...  
Keyword(s):  
De Novo ◽  
Model Organisms

scholarly journals Regulating the Regulators: Mechanisms of Substrate Selection of the O-GlcNAc Cycling Enzymes OGT and OGA

Glycobiology ◽  
2021 ◽  
Author(s):  
Hannah M Stephen ◽  
Trevor M Adams ◽  
Lance Wells
Keyword(s):  
Nutrient Sensing ◽  
Substrate Selection ◽  
Disease States ◽  
Dynamic Modification ◽  
Selection For ◽  
Outstanding Question ◽  
Glcnac Transferase ◽  
Future Work ◽  
Partner Proteins ◽  
Selection Of

Abstract Thousands of nuclear and cytosolic proteins are modified with a single β-N-acetylglucosamine on serine and threonine residues in mammals, a modification termed O-GlcNAc. This modification is essential for normal development and plays important roles in virtually all intracellular processes. Additionally, O-GlcNAc is involved in many disease states, including cancer, diabetes, and X-linked intellectual disability. Given the myriad of functions of the O-GlcNAc modification, it is therefore somewhat surprising that O-GlcNAc cycling is mediated by only two enzymes: the O-GlcNAc transferase (OGT), which adds O-GlcNAc, and the O-GlcNAcase (OGA), which removes it. A significant outstanding question in the O-GlcNAc field is how do only two enzymes mediate such an abundant and dynamic modification. In this review, we explore the current understanding of mechanisms for substrate selection for the O-GlcNAc cycling enzymes. These mechanisms include direct substrate interaction with specific domains of OGT or OGA, selection of interactors via partner proteins, posttranslational modification of OGT or OGA, nutrient sensing, and localization alteration. Altogether, current research paints a picture of an exquisitely regulated and complex system by which OGT and OGA select substrates. We also make recommendations for future work, toward the goal of identifying interaction mechanisms for specific substrates that may be able to be exploited for various research and medical treatment goals.

scholarly journals In Search of Species-Specific SNPs in a Non-Model Animal (European Bison (Bison bonasus))—Comparison of De Novo and Reference-Based Integrated Pipeline of STACKS Using Genotyping-by-Sequencing (GBS) Data

Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2226
Author(s):  
Sazia Kunvar ◽  
Sylwia Czarnomska ◽  
Cino Pertoldi ◽  
Małgorzata Tokarska
Keyword(s):  
Reference Genome ◽  
De Novo ◽  
Bos Taurus ◽  
Model Organism ◽  
Genotyping By Sequencing ◽  
Model Organisms ◽  
European Bison ◽  
Model Animal ◽  
Pcr Duplicates ◽  
Species Specific

The European bison is a non-model organism; thus, most of its genetic and genomic analyses have been performed using cattle-specific resources, such as BovineSNP50 BeadChip or Illumina Bovine 800 K HD Bead Chip. The problem with non-specific tools is the potential loss of evolutionary diversified information (ascertainment bias) and species-specific markers. Here, we have used a genotyping-by-sequencing (GBS) approach for genotyping 256 samples from the European bison population in Bialowieza Forest (Poland) and performed an analysis using two integrated pipelines of the STACKS software: one is de novo (without reference genome) and the other is a reference pipeline (with reference genome). Moreover, we used a reference pipeline with two different genomes, i.e., Bos taurus and European bison. Genotyping by sequencing (GBS) is a useful tool for SNP genotyping in non-model organisms due to its cost effectiveness. Our results support GBS with a reference pipeline without PCR duplicates as a powerful approach for studying the population structure and genotyping data of non-model organisms. We found more polymorphic markers in the reference pipeline in comparison to the de novo pipeline. The decreased number of SNPs from the de novo pipeline could be due to the extremely low level of heterozygosity in European bison. It has been confirmed that all the de novo/Bos taurus and Bos taurus reference pipeline obtained SNPs were unique and not included in 800 K BovineHD BeadChip.

scholarly journals Transcriptomic analyses of the termite, Cryptotermes secundus, reveal a gene network underlying a long lifespan and high fecundity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Silu Lin ◽  
Jana Werle ◽  
Judith Korb
Keyword(s):  
Life History ◽  
Social Insects ◽  
Social Communication ◽  
Gene Network ◽  
Social Insect ◽  
Nutrient Sensing ◽  
Model Organisms ◽  
Termite Species ◽  
High Fecundity ◽  
Trade Off

AbstractOrganisms are typically characterized by a trade-off between fecundity and longevity. Notable exceptions are social insects. In insect colonies, the reproducing caste (queens) outlive their non-reproducing nestmate workers by orders of magnitude and realize fecundities and lifespans unparalleled among insects. How this is achieved is not understood. Here, we identified a single module of co-expressed genes that characterized queens in the termite species Cryptotermes secundus. It encompassed genes from all essential pathways known to be involved in life-history regulation in solitary model organisms. By manipulating its endocrine component, we tested the recent hypothesis that re-wiring along the nutrient-sensing/endocrine/fecundity axis can account for the reversal of the fecundity/longevity trade-off in social insect queens. Our data from termites do not support this hypothesis. However, they revealed striking links to social communication that offer new avenues to understand the re-modelling of the fecundity/longevity trade-off in social insects.

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